CN113166114A

CN113166114A - Cyclic tetramer compounds as proprotein convertase subtilisin/KEXIN 9 type (PCSK9) inhibitors for the treatment of metabolic disorders

Info

Publication number: CN113166114A
Application number: CN201980076002.XA
Authority: CN
Inventors: K·布林纳; B·A·德克里斯托弗; A·N·弗莱尔; A·A·戈洛索夫; P·格罗舍; E·Y·刘; J·Y·C·毛; L·G·莫诺维奇; T·J·帕特尔; C·C·桑切斯; 苏连胜; 杨莉华; 郑锐
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2018-11-27
Filing date: 2019-11-26
Publication date: 2021-07-23
Also published as: ECSP21036194A; US11813306B2; PH12021551049A1; DOP2021000100A; AU2019387294B2; WO2020110009A1; US11026993B2; UY38485A; TW202038990A; CO2021006895A2; CA3115960A1; MA54284A; PE20211658A1; EP3887365A1; BR112021009857A2; KR20210096154A; US20200164024A1; CL2021001365A1; JOP20210120A1; US20210252103A1

Abstract

The present disclosure relates to PCSK9 inhibitors useful for the treatment of cholesterol lipid metabolism and other diseases in which PCSK9 plays a role, said PCSK9 inhibitors having formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide or tautomer thereof, wherein R is₁、R₁、R₁、R₁、R₁、R₁、R₁、R₁、R₁、X₁、X₂And X₃Described herein.

Description

Cyclic tetramer compounds as proprotein convertase subtilisin/KEXIN 9 type (PCSK9) inhibitors for the treatment of metabolic disorders

Cross Reference to Related Applications

This application claims the benefit and priority of U.S. provisional application No. 62/772,030 filed on 27.11.2018 and U.S. provisional application No. 62/924,828 filed on 23.10.2019, which are incorporated herein by reference in their entirety.

Technical Field

The present disclosure relates to modulators of proprotein convertase subtilisin/kexin type 9 (PCSK9) for use in the treatment of diseases or disorders associated with PCSK9 protease. In particular, the disclosure relates to compounds and compositions that inhibit PCSK9, methods of treating diseases or disorders associated with PCSK9, and methods of synthesis of these compounds.

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the subtilisin serine protease family of secreted subtilases, and is expressed in many tissues and cell types. The PCSK9 protein comprises a signal sequence, a prodomain, a catalytic domain comprising conserved residue triplets (D186, H226 and S386) and a C-terminal domain, and is synthesized as a soluble 74kDa precursor, which undergoes autocatalytic cleavage in the endoplasmic reticulum. It has been shown that secretion requires autocatalytic activity.

PCSK9 has a significant effect on plasma low density lipoprotein cholesterol (LDL-C) levels by modulating the liver Low Density Lipoprotein Receptor (LDLR), a major pathway for cholesterol removal from the circulatory system. PCSK9 binds to LDLR and directs it to lysosomal degradation, thereby increasing plasma LDL-C levels, which in turn increases Coronary Heart Disease (CHD) risk. (Maxwell K.N., Proc. Natl. Acad. Sci. [ Proc. Sci. USA ]101,2004,7100- & 7105; Park, S.W., J.biol. chem. [ J.Biochem. ]279,2004,50630- & 50638; Lagace T.A., et al J.Clin. invest. [ J.Clin. Clin. [ J.Clin.C. ]2006,116(11):2995- & 3005). Overexpression of mouse or human PCSK9 in mice has been shown to increase total LDL-C levels and substantially reduce liver LDLR protein, while no effect on mRNA, SREBP or SREBP protein nuclear-to-cytoplasmic ratios was observed. (Maxwell K.N., Proc. Natl.Acad.Sci. [ Proc. Natl.Acad. ]101,2004, 7100-. In addition, PCSK9 mutations that cause loss of PCSK9 function in a mouse model have also been shown to reduce total and LDL-C levels. (Cohen, J.C., et al, N.Engl.J.Med. [ New England journal of medicine ],354,2006, 1264-. Thus, the results indicate that modulation of PCSK9 results in decreased LDLR protein levels.

Gene deletion of PCSK9 has also been performed in mice. PCSK9 knockout mice show about a 50% reduction in plasma cholesterol levels and enhanced sensitivity to statins in lowering plasma cholesterol (rashed, s., et al, proc.natl.acad.sci. [ proceedings of the american academy of sciences ],2005,102: 5374-. Human genetic data strongly supports the role of PCSK9 in LDL balance. The link between PCSK9 and plasma LDL-C levels was first established by finding PCSK9 missense mutations in autosomal dominant familial hypercholesterolemia patients (abiladel, m., et al, Nature [ Nature ],2003,34: 154-6). Patients carrying the PCSK9 gain-of-function allele had increased plasma LDL-C levels and premature CHD, whereas patients having the PCSK9 loss-of-function allele had significantly reduced plasma LDL-C and were protected from CHD.

PCSK9 also plays a role in lipoprotein (a) (lp (a)) metabolism. Lp (a) is an atherogenic lipoprotein, consisting of LDL particles covalently linked to apolp (a). Human genetic studies have shown that lp (a) is causally related to CHD risk. PCSK9 therapeutic antibodies have been shown to significantly reduce lp (a) levels in hypercholesterolemic patients. (Desai, N.R., et al, Circulation. [ Loop ]2013,128(9): 962-. Patients receiving statin therapy treated with a monoclonal antibody directed to PCSK9 showed up to a 32% reduction in lp (a) levels compared to placebo. (Desai N.R., et al, Circulation. [ cycle ]2013,128(9): 962-.

In addition to its cardiovascular effects, PCSK9 plays an important role in sepsis, a life-threatening disease caused by the body's response to infection. Overexpression of PSCK9 in septic mice has been shown to exacerbate sepsis by increasing inflammation, while inhibition of PCSK9 has been shown to reduce mortality. (Dwivedi, D.J., et al, Shock,2016,46(6), 672-. Furthermore, flow cytometry studies in human HepG2 cells showed that PCSK9 negatively regulates gram-negative Lipopolysaccharide (LPS) uptake by hepatocytes by modulating LDLR-mediated bacterial lipid uptake of lipoteichoic acid (LTA) and LPS through an LDL-dependent mechanism. (Grin, p.m., et al, Nature [ Nature ],2018,8(1):10496) inhibition of PCSK9 thus has the potential to treat sepsis by reducing the body's immune response to infection.

Currently, there are no known small molecule inhibitors of PCSK 9. The only known PCSK9 inhibitor on the market is the anti-PCSK 9 antibody. Therefore, inhibition of PCSK9 using small molecule inhibitors has potential for the treatment of a range of diseases including hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, triglyceride-rich lipoprotein (TRL), triglyceride elevation, sepsis, xanthoma, and other diseases. For these reasons, there remains a need for novel and effective small molecule PCSK9 inhibitors.

Disclosure of Invention

A first aspect of the present disclosure relates to a compound having formula (I):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

X₁and X₂Each independently is H or (C)₁-C₆) Alkyl, or X₁And X₂Together with the carbon atom to which they are attached form ═ (O);

X₃is-CH₂- (when X)₁And X₂Each independently is H or (C)₁-C₆) Alkyl, or X₁And X₂Together with the carbon atom to which they are attached form ═ (O), or X₃is-O-, -NH-or-N (C)₁-C₆) Alkyl- (when X)₁And X₂When taken together with the carbon atom to which they are attached to form ═ (O);

R₁is (C)₆-C₁₀) Aryl OR 5-OR 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are-OR₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one or more R₁₁Substitution;

R₂is H, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) Carbocyclyl group, (C)₃-C₇) Cycloalkenyl, 5-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, (C)₆-C₁₀) Aryl, or a 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the alkyl is optionally substituted with one or more R₁₈And said carbocyclyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R ₁₉Substitution;

R₃is H, D, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, or (C)₁-C₆) Hydroxyalkyl, wherein the alkyl is optionally substituted with one or more R₁₄Substitution;

R₄is H or (C)₁-C₆) An alkyl group; or

R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring comprising 1-3 heteroatoms selected from N, O and S;

R₅and R₇Each independently H, D, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy radicalBase, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, or (C)₁-C₆) Hydroxyalkyl group wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more D;

R₆is (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, or (C)₁-C₆) Hydroxyalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group;

R₈is H, (C)₁-C₆) Alkyl, or (C)₁-C₆) Haloalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of: (C)₃-C₇) Carbocyclyl, 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, -NR₁₆R₁₇and-C (O) NR₁₆R₁₇；

R₉Is halogen, (C)₁-C₆) Alkyl, (C) ₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, or CN;

R₁₀is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one or more R₂₂Substitution;

each R₁₁Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, or CN;

R₁₂and R₁₃Each independently is H or (C)₁-C₆) An alkyl group;

each R₁₄D, NR independently at each occurrence₁₅R_15'、(C₃-C₇) A carbocyclyl, or a 3-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, and (C)₁-C₆) A haloalkoxy group;

R₁₅and R_15'Each independently is H or (C)₁-C₆) An alkyl group;

R₁₆and R₁₇Each independently is H or (C)₁-C₆) Alkyl, or

R₁₆And R₁₇Together with the nitrogen atom to which they are attached form a 4-to 7-membered heterocyclyl ring optionally containing 1-2 additional heteroatoms selected from N, O and S;

each R₁₈Independently at each occurrence is (C)₃-C₇) Carbocyclyl, 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C) ₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R₂₀Substitution;

each R₁₉Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, or CN; or

Two R₁₉When on adjacent atoms form together (C)₆-C₁₀) Aryl or a 5-or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH and CN;

each R₂₀Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, oxo, -OH, or CN; or

When R is₁₈When it is carbocyclic or heterocyclic, two R₂₀When attached to the same carbon atom, together form ═ (O);

R₂₁is H or (C)₁-C₆) An alkyl group;

each R₂₂Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, CN, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one or more R ₂₃Substitution;

each R₂₃Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -CH₂(OCH₂CH₂)_1-3OCH₂CH₃-OH, CN, or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, wherein the heterocyclyl is optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl group isQuilt of choice-NR₂₄R₂₅Substituted, or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one or more substituents each independently selected from halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂) (ii) a And is

R₂₄And R₂₅Each independently is H, (C)₁-C₆) Alkyl, or optionally substituted by one to two (C)₁-C₆) Alkyl substituted (C)₃-C₇) A carbocyclic group;

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide or tautomer thereof.

In another aspect, the disclosure relates to compounds having formula (I), wherein:

R₂is H, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl radical、(C₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) Carbocyclyl group, (C)₃-C₇) Cycloalkenyl, 5-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, (C)₆-C₁₀) Aryl, or a 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the alkyl is optionally substituted with one or more R₁₈And said carbocyclyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R₁₉Substitution;

R₃is H, D, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, or (C)₁-C₆) Hydroxyalkyl, wherein the alkyl is optionally substituted with one or more R ₁₄Substitution;

R₄is H or (C)₁-C₆) An alkyl group; or

R₅and R₇Each independently H, D, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, or (C)₁-C₆) Hydroxyalkyl group wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more D;

R₉Is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, or CN;

R₁₀is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one or more R ₂₂Substitution;

R₁₂and R₁₃Each independently is H or (C)₁-C₆) An alkyl group;

R₁₅and R_15'Each independently is H or (C)₁-C₆) An alkyl group;

R₁₆and R₁₇Each independently of the otherGround is H or (C)₁-C₆) Alkyl, or

R₁₆And R₁₇Together with the nitrogen atom to which they are attached form a 4-to 7-membered heterocyclyl ring comprising 1-2 additional heteroatoms selected from N, O and S;

each R₁₈Independently at each occurrence is (C)₃-C₇) Carbocyclyl, 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R₂₀Substitution;

each R₁₉Independently at each occurrence, is halogen, (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, or CN; or

R₂₁is H or (C)₁-C₆) An alkyl group;

each R₂₂Independently at each occurrence is halogen,(C₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, CN, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one or more R₂₃Substitution;

each R₂₃Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C) ₁-C₆) Haloalkoxy, -CH₂(OCH₂CH₂)_1-3OCH₂CH₃-OH, CN, or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, wherein the heterocyclyl is optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted, or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one or more substituents each independently selected from halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂) (ii) a And is

R₂₄And R₂₅Each independently is H, (C)₁-C₆) Alkyl, or (C)₃-C₇) A carbocyclic group;

Another aspect of the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt thereof, for use in treating, preventing, ameliorating or delaying the progression of a PCSK 9-mediated disease or disorder or for use in treating, preventing, ameliorating or delaying the progression of a disease or disorder in which inhibition of PCSK9 or PCSK9 activity is desired.

In another aspect, the disclosure relates to the use of a compound having formula (I), or a pharmaceutically acceptable salt thereof, for treating, preventing, ameliorating or delaying the progression of a PCSK 9-mediated disease or disorder or for treating, preventing, ameliorating or delaying the progression of a disease or disorder in which inhibition of PCSK9 or PCSK9 activity is desired.

Another aspect of the present disclosure relates to the use of a compound having formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, ameliorating or delaying the progression of a PCSK 9-mediated disease or disorder or for treating, preventing, ameliorating or delaying the progression of a disease or disorder in which inhibition of PCSK9 or PCSK9 activity is desired.

In another aspect, the disclosure relates to a method for treating, preventing, ameliorating or delaying the progression of a PCSK 9-mediated disease or disorder, the method comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound according to the present disclosure having formula (I), or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a method of treating, preventing, ameliorating or delaying the progression of a PCSK 9-mediated disease or disorder or a disease or disorder for which inhibition of PCSK9 or PCSK9 activity is desired, the method comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound according to the present disclosure having formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure relates to a method of treating, preventing, inhibiting or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, sepsis, elevated lp (a), elevated LDL, elevated TRL or elevated triglycerides, the method comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a method of (i) reducing lp (a), (ii) reducing lp (a) plasma levels, (iii) reducing lp (a) serum levels, (iv) reducing serum TRL or LDL levels, (v) reducing serum triglyceride levels, (vi) reducing LDL-C, (vii) reducing the total concentration of plasma apoB, (viii) reducing LDL apoB, (ix) reducing TRL apoB, or (x) reducing non-HDL-C, the method comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure also relates to a method of (I) lowering LDL-C, (ii) lowering total apolipoprotein b (apoB), (iii) lowering LDL apoB, (iv) lowering TRL apoB or (v) lowering non-HDL-C, and combinations thereof, in a patient in need thereof, wherein said method comprises administering to said patient a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a method of reducing total plasma concentration of a marker selected from the group consisting of: (i) (iii) LDL-C, (ii) apoB, (iii) LDL apoB, (iv) TRL apoB and (v) non-HDL-C and combinations thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a pharmaceutical composition comprising (e.g., a therapeutically effective amount of) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

Another aspect of the disclosure relates to a pharmaceutical composition comprising (e.g., a therapeutically effective amount of) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, for use in treating a PCSK 9-mediated disease or disorder.

In another aspect, the disclosure relates to a method of modulating PCSK9 comprising administering to a patient in need thereof a compound having formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a method of inhibiting PCSK9 comprising administering to a patient in need thereof a compound having formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure relates to a method of inhibiting PCSK9 activity comprising administering to a patient in need thereof a compound having formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure relates to a method of treating a PCSK 9-mediated disease or disorder, the method comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a method of reducing LDL-C in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt thereof, thereby reducing LDL-C in the patient.

In another aspect, the disclosure relates to compounds having formula (I) or a pharmaceutically acceptable salt thereof, for use in treating a PCSK 9-mediated disease or disorder.

Another aspect of the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a PCSK 9-mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis and xanthoma.

In another aspect, the disclosure relates to the use of a compound having formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a PCSK 9-mediated disease or disorder.

Another aspect of the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease associated with the inhibition of PCSK9 activity.

In another aspect, the disclosure relates to the use of a compound having formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of diseases associated with the inhibition of PCSK9 activity.

In certain aspects, PCSK9 modulating or inhibiting compounds of the present disclosure may be administered alone or in combination with other compounds (including other PCSK9 modulating or inhibiting agents) or other therapeutic agents.

Thus, in another aspect, the disclosure relates to a combination comprising (e.g., a therapeutically effective amount of) a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutically active agents.

Another aspect of the present disclosure relates to a process for preparing a compound having formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

Wherein R is_a1And R₅Each independently is (C)₁-C₆Alkyl) and R₉Is as defined above for formula (I), the method comprising:

(a) alkylating a compound having formula (IIa) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

wherein R is₅Is H and R₉As defined above for formula (I),

the alkylation is carried out using an alkyl halide (e.g., methyl iodide, ethyl iodide, etc.) and a base (e.g., NaH) in a solvent (e.g., DMF, acetonitrile, etc.) at low temperature to provide a compound having formula (IIb),

wherein R is₅Is (C)₁-C₆Alkyl) and R₉Is as defined above for formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

(b) reacting a compound having formula (IIb) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof with an acid (e.g., trifluoroacetic acid) in a solvent (e.g., dichloromethane), followed by Boc₂Reacting O with a base, such as N, N-Diisopropylethylamine (DIPEA), to form a compound having formula (IIc),

wherein R is₅Is (C)₁-C₆Alkyl) and R₉Is as defined above for formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof;

(c) Alkylating a compound having formula (IIc), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, with an alkylating agent (e.g., methyl iodide, ethyl iodide, etc.) in a solvent (e.g., DMF, acetonitrile, etc.) and optionally a metal oxide (e.g., silver (I) oxide (AgO), etc.) to provide a compound having formula (IId),

wherein R is_a1And R₅Each independently is (C)₁-C₆Alkyl) and R₉Is as defined above for formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof;and

(d) with a palladium catalyst (e.g. tetrakis (triphenylphosphine) palladium (0) (Pd (PPh)₃)₄) Etc.) and N, N-dimethyltrimethylsilylamine in a solvent (e.g., DCM, etc.) to dealkylate the compound having formula (IId) to provide the compound having formula (II). In one embodiment, the palladium catalyst is tetrakis (triphenylphosphine) palladium (0) (Pd (PPh)₃)₄)。

In another aspect, the disclosure relates to a method of making a compound having formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,

wherein R is _a1Is H, R₅Is (C)₁-C₆Alkyl) and R₉Is as defined above for formula (I), the method comprising reacting a compound having formula (IIb):

wherein R is₅Is (C)₁-C₆Alkyl) and R₉Is as defined above for formula (I) with a palladium catalyst (e.g. tetrakis (triphenylphosphine) palladium (0) (Pd (PPh)₃)₄) Etc.) N, N-dimethyltrimethylsilylamine is reacted in a solvent (e.g., DCM, etc.) to provide a compound having formula (II). In one embodiment, the palladium catalyst is tetrakis (triphenylphosphine) palladium (0) (Pd (PPh)₃)₄)。

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not to be considered as prior art to the claimed disclosure. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the disclosure will be apparent from the following detailed description, and from the claims.

Detailed Description

The present disclosure relates to compounds and compositions capable of modulating PCSK9 activity. The disclosure features methods of treating, preventing, or ameliorating diseases or disorders in which PCSK9 plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof. The methods of the present disclosure may be used to treat a variety of PCSK 9-dependent diseases and disorders by modulating or inhibiting PCSK 9. Inhibiting or modulating PCSK9 provides a novel method for treating, preventing or ameliorating diseases including, but not limited to, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease (including aortic and cerebrovascular disease), peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis and xanthoma.

The compounds of the present disclosure have utility in the treatment of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation (e.g., VLDL and/or chylomicron elevation), triglyceride elevation, sepsis and xanthoma through the inhibition of PCSK 9.

For example, compounds of the present disclosure having formula (I) bind to PCSK9 and thus inhibit PCSK9 and/or PCSK9 activity because PCSK9 is no longer capable of binding to Low Density Lipoprotein Receptor (LDLR) or any other target receptor. For example, if PCSK9 is blocked, more LDLR is circulated and present at the cell surface to remove LDL particles from the extracellular fluid. Thus, blocking PCSK9 may reduce LDL particle concentration in blood.

Accordingly, the compounds of the present disclosure are therefore potentially useful for treating, preventing, ameliorating or delaying the progression of PCSK 9-mediated diseases or disorders or diseases or disorders in which PCSK9 plays a role, as well as the progression of conditions, diseases and disorders that benefit from modulation of PCSK9 or PCSK9 activity.

Furthermore, the compounds of the present disclosure are therefore potentially useful for treating, preventing, ameliorating or delaying the progression of a disease or disorder in which inhibition of PCSK9 or PCSK9 activity is desired.

Such diseases and disorders include diseases or disorders selected from the group consisting of: hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated lp (a), elevated LDL, elevated TRL (e.g., elevated VLDL and/or chylomicron), elevated triglycerides, sepsis, and xanthoma.

Various embodiments of the present disclosure are described herein. It will be appreciated that the features specified in each embodiment can be combined with other specified features of other embodiments to provide further embodiments.

In a first aspect of the disclosure, compounds having formula (I) are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides and tautomers thereof, wherein R is₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉、X₁、X₂And X₃As described above.

The details of the present disclosure are set forth in the description appended below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In this specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are herein incorporated by reference in their entirety.

Definitions of terms and conventions used

Terms not explicitly defined herein should be understood to have meanings that would be apparent to those skilled in the art in light of the present disclosure and the context. However, unless indicated to the contrary, the following terms, as used in the present specification and appended claims, have the indicated meanings and follow the following conventions.

Chemical nomenclature, terminology, and conventions

In a group (radical) or moiety defined below, the number of carbon atoms is generally indicated before the group, and is for example (C)₁-C₁₀) Alkyl means an alkyl group having 1 to 10 carbon atoms. In general, for groups containing two or more subgroups, the last-mentioned group is the point of attachment of the group, e.g., "alkylaryl" means a monovalent group of the formula alkyl-aryl-, and "arylalkyl" means a monovalent group of the formula aryl-alkyl-. Furthermore, the use of terms denoting a monovalent group, wherein a divalent group is suitable, is to be understood as denoting the corresponding divalent group, and vice versa. Unless otherwise indicated, the conventional definitions of the term control and the conventional valencies of the stabilizing atoms are assumed and are embodied in all formulae and groups. The articles "a" and "an" as used in this disclosure mean one or more than one (e.g., at least one) of the grammatical object of the article. By way of example, "an element" means that one element Or more than one element.

The term "and/or" as used in this disclosure means "and" or "unless otherwise indicated.

The term "optionally substituted" means that a given chemical moiety (e.g., an alkyl group) can be, but is not required to be, bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (e.g., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have a substituent other than hydrogen. For example, it may be bonded at any position along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any other functional groups. Suitable substituents for optional substitution of the groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH₂CN、-O-(C₁-C₆) Alkyl, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -O- (C)₂-C₆) Alkenyl, -O- (C)₂-C₆) Alkynyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, -OH, -OP (O) (OH)₂、-OC(O)(C₁-C₆) Alkyl, -C (O) (C)₁-C₆) Alkyl, -OC (O) O (C) ₁-C₆) Alkyl, -NH₂、-NH((C₁-C₆) Alkyl), -N ((C)₁-C₆) Alkyl radical)₂、-NHC(O)(C₁-C₆) Alkyl, -C (O) NH (C)₁-C₆) Alkyl, -S (O)₂(C₁-C₆) Alkyl, -S (O) NH (C)₁-C₆) Alkyl, and S (O) N ((C)₁-C₆) Alkyl radical)₂. The substituents themselves may be optionally substituted. As used herein, "optionally substituted" also refers to substituted or unsubstituted, the meaning of which is described below.

The term "substituted" means that the specified group or moiety bears one or more suitable substituents, wherein a substituent may be attached to the specified group or moiety at one or more positions. For example, an aryl group substituted with a cycloalkyl group can indicate that the cycloalkyl group is connected to one atom of the aryl group by a bond or is fused to the aryl group and shares two or more common atoms.

The term "unsubstituted" means that the specified group bears no substituents.

Unless specifically defined otherwise, "aryl" means a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings (including monocyclic or bicyclic groups), such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group are optionally linked (e.g., biphenyl) or fused (e.g., naphthyl) at a single point. The aryl group is optionally substituted at any point of attachment with one or more substituents, for example 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -CN, -O- (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkyl, -O- (C)₂-C₆) Alkenyl, -O- (C)₂-C₆) Alkynyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, -OH, -OP (O) (OH)₂、-OC(O)(C₁-C₆) Alkyl, -C (O) (C)₁-C₆) Alkyl, -OC (O) O (C)₁-C₆) Alkyl, NH₂、NH((C₁-C₆) Alkyl), N ((C)₁-C₆) Alkyl radical)₂、-S(O)₂-(C₁-C₆) Alkyl, -S (O) NH (C)₁-C₆) Alkyl, and S (O) N ((C)₁-C₆) Alkyl radical)₂. The substituents themselves are optionally substituted. Further, when containing two fused rings, the aryl group optionally has an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems for these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalkenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzorenyl, and the like.

Unless otherwise specifically defined, "heteroaryl" means 5 toA monovalent monocyclic or polycyclic aromatic group of 24 ring atoms containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Heteroaryl as defined herein also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, or S. The aromatic groups are optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl N-oxide, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thien-2-yl, benzopyridyl (quinolyl), benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno [3,2-b ] oxide ]Thiophene, triazolyl, triazinyl, imidazo [1,2-b ]]Pyrazolyl, fluoro [2,3-c ]]Pyridyl, imidazo [1,2-a ]]Pyridyl, indazolyl, pyrrolo [2,3-c ]]Pyridyl, pyrrolo [3,2-c]Pyridyl, pyrazolo [3,4-c]Pyridyl, thieno [3,2-c]Pyridyl, thieno [2,3-c ]]Pyridyl, thieno [2,3-b ]]Pyridyl, benzothiazolyl, indolyl, indolinyl, indolonyl, dihydrobenzothienyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxazinyl, quinolinyl, isoquinolinyl, 1, 6-naphthyridinyl, benzo [ de ] de]Isoquinolinyl, pyrido [4,3-b ]][1,6]Naphthyridinyl, thieno [2,3-b ]]Pyrazinyl, quinazolinyl, tetrazolo [1,5-a ]]Pyridyl, [1,2,4 ] or a salt thereof]Triazolo [4,3-a]Pyridyl, isoindolyl, pyrrolo [2,3-b ]]Pyridyl, pyrrolo [3,4-b]Pyridyl, pyrrolo [3,2-b]Pyridyl, imidazo [5,4-b ]]Pyridyl, pyrrolo [1,2-a ]]Pyrimidinyl, tetrahydropyrrolo [1,2-a ] s]Pyrimidinyl, 3, 4-dihydro-2H-1. DELTA²-pyrrolo [2,1-b]Pyrimidine, dibenzo [ b, d ]]Thiophene, pyridine-2-ones, fluorine [3,2-c]Pyridyl, fluoro [2,3-c ] ]Pyridyl, 1H-pyrido [3,4-b ]][1,4]Thiazinyl, benzoxazolyl, benzisoxazolyl, fluoro [2,3-b]Pyridyl, benzothiophenyl, 1, 5-naphthyridinyl, fluoro [3,2-b ]]Pyridine, [1,2,4 ]]Triazolo [ l,5-a]Pyridyl, benzo [1,2,3 ] s]Triazolyl, imidazo [1,2-a ]]Pyrimidinyl, [1,2,4 ] or their salts]Triazolo [4,3-b]Pyridazinyl, benzo [ c)][1,2,5]Thiadiazolyl, benzo [ c ]][1,2,5]Oxadiazole, 1, 3-dihydro-2H-benzo [ d]Imidazol-2-one, 3, 4-dihydro-2H-pyrazolo [1,5-b][1,2]Oxazinyl, 4,5,6, 7-tetrahydropyrazolo [1,5-a]Pyridyl, thiazolo [5,4d ]]Thiazolyl, imidazo [2,1-b ]][1,3,4]Thiadiazolyl, thieno [2,3-b ]]Pyrrolyl, 3H-indolyl, and derivatives thereof. Further, when containing two fused rings, the aryl groups defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems for these heteroaryl groups include indolinyl, indolonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3, 4-dihydro-lH-isoquinolinyl, 2, 3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxazinyl.

Halogen or "halo" means fluoro, chloro, bromo, or iodo.

"alkyl" means a straight or branched chain saturated hydrocarbon containing from 1 to 12 carbon atoms. (C)₁-C₆) Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

"alkoxy" means a straight or branched chain saturated hydrocarbon containing from 1 to 12 carbon atoms, which contains a terminal "O" in the chain, such as-O (alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.

"alkenyl" means a straight or branched chain unsaturated hydrocarbon containing from 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of the alkenyl group may be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutene, pentenyl, or hexenyl. Alkenyl groups may be unsubstituted or substituted, and may be straight or branched.

"alkynyl" means a straight or branched chain unsaturated hydrocarbon containing from 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, or hexynyl. Alkynyl groups may be unsubstituted or substituted.

"cycloalkyl" means a monocyclic or polycyclic saturated carbocyclic ring containing from 3 to 18 carbon atoms. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptan-yl, cyclooctyl, norbornyl (norbomanyl), norbornenyl, bicyclo [2.2.2 ] n-yl]Octyl, or bicyclo [2.2.2]Octenyl and derivatives thereof. (C)₃-C₈) Cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. Cycloalkyl groups may be fused (e.g., decalin) or bridged (e.g., norbornadiene (norbomane)).

"carbocyclyl" refers to a monocyclic or polycyclic, saturated or partially unsaturated carbocyclic ring containing 3 to 18 carbon atoms (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, etc.). Examples of carbocyclyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclobutene, cyclopentyl, cyclopentene, cyclohexyl, cyclohexene, cycloheptyl, cyclooctyl, norbornyl (norbomanyl), norbornenyl (norbomenyl), bicyclo [2.2.2]Octyl, or bicyclo [2.2.2]Octenyl and derivatives thereof. (C)₃-C₈) Carbocyclyl is a carbocyclyl group containing between 3 and 8 carbon atoms. Carbocyclyl groups may be fused (e.g., decalin) or bridged (e.g., norbornadiene (norbomane)).

The term "cycloalkenyl" refers to partially unsaturated carbocyclic rings containing 3 to 18 carbon atoms, preferably 4 to 12 carbons, and 1 or 2 double bonds. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, and cycloheptadienyl. (C)₃-C₈) Cycloalkenyl is cycloalkenyl containing from 3 to 8 carbon atoms and at least one double bond.

"heterocycloalkyl" means a saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen or sulfur (O, N or S), and in which there is no shared delocalized n-electron (aromaticity) between the ring carbons or heteroatoms. The heterocycloalkyl ring structure may be substituted with one or more substituents. The substituents themselves may beTo be optionally substituted. Examples of heterocycloalkyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxanyl, piperidinyl, morpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azanyl

Oxygen radical and oxygen radical

Radical diaza

Examples of the substituent include a phenyl group, a tropyl group, an oxazolidone group, a 1, 4-dioxanyl group, a dihydrofuryl group, a 1, 3-dioxolanyl group, an imidazolidinyl group, an imidazolinyl group, a dithiolanyl group, and a homotropyl group (homotropanyl group).

"heterocyclyl" means a saturated (e.g., heterocycloalkyl ring) or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (O, N or S), and in which there is no delocalized n-electron (aromaticity) shared between the ring carbons or heteroatoms. The heterocyclyl ring structure may be substituted with one or more substituents. The substituents themselves may be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, dihydropyrrolidinyl, pyridin-2 (1H) -one, dihydropyridinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxanyl, piperidinyl, morpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azanyl, dihydropyrrolidinyl, dihydromorpholinyl, pyridin-2 (1H) -one, dihydropyridinyl, oxazolinyl, thiazolidinyl, thiazolinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxanyl, piperidinyl, morpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, and morpholinyl

Oxygen radical and oxygen radical

Radical diaza

"hydroxyalkyl" means an alkyl group substituted with one or more-OH groups. Examples of hydroxyalkyl radicals include HO-CH₂-、HO-CH₂CH₂-, and CH₂-CH(OH)-。

"haloalkyl" means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

"haloalkoxy" means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

"cyano" means a substituent having a nitrogen atom and a carbon atom connected by a triple bond, such as C.ident.N.

The term "oxo" as used herein refers to "-O

A "group.

The term "N-oxide" refers to an oxygen atom bonded to a nitrogen atom (e.g., N-O) by a single bond (e.g., "oxo")

)。

"amino" means a substituent containing at least one nitrogen atom (e.g., NH)₂)。

Salt, prodrug, derivative, and solvate terms and conventions

By "prodrug" or "prodrug derivative" is meant a covalently bonded derivative or carrier of a parent compound or active drug substance that undergoes at least some biotransformation before exhibiting one or more of its pharmacological effects. In general, such prodrugs have metabolically cleavable groups and are rapidly converted in vivo to yield the parent compound, for example by hydrolysis in the blood, and typically include ester and amide analogs of the parent compound. Prodrugs are formulated with the goal of improving chemical stability, improving patient acceptance and compliance, improving bioavailability, prolonging time of action, improving organ selectivity, improving formulation (e.g., increased aqueous solubility), and/or reducing side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under normal conditions. Prodrugs can be readily prepared from the parent compound by methods known in the art, such as those described in: a Textbook of Drug Design and Development [ Textbook of Drug Design and Development ], Krogsgaard-Larsen and H.Bundgaard (ed.), Gordon & Breach [ Goden and Bridgy Press ],1991, in particular chapter 5 "Design and Applications of Prodrugs [ Design and use of Prodrugs ]"; design of produgs [ Design of prodrug ], h.bundgaard (editions), Elsevier [ eisweil group ], 1985; prodrug: Topical and Ocular Drug Delivery [ prodrug: topical and ocular drug delivery ], k.b. sloan (editors), Marcel Dekker [ massel Dekker ], 1998; methods in Enzymology [ Methods in Enzymology ], K.Widder et al (eds.), Vol.42, Academic Press [ Academic Press ],1985, especially pages 309 and 396; burger's Medicinal Chemistry and Drug Discovery, 5 th edition, M.Wolff (eds.), John Wiley & Sons [ John Willi father publishing company ],1995, particularly Vol.1 and pp.172-; Pro-Drugs as Novel Delivery Systems, t.higuchi and v.stella (ed.), am.chem.soc. [ proceedings of the american society of chemists ], 1975; bioreversible Carriers in Drug Design [ Bioreversible vector in Drug Design ], e.b. roche (ed.), Elsevier [ eisavir group ],1987, each of which is incorporated herein by reference in its entirety.

As used herein, "pharmaceutically acceptable prodrug" means a prodrug of a compound of the present disclosure that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for its intended use and zwitterionic forms, where possible.

By "salt" is meant the ionic form of the parent compound or the product of a reaction between the parent compound and a suitable acid or base to produce an acid or base salt of the parent compound. Salts of the compounds of the present disclosure can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, salts are prepared by reacting the free basic or acidic parent compound with a stoichiometric amount or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or different combination of solvents.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the present disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, typically water-or oil-soluble or dispersible, and effective for its intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds of the present disclosure are useful in both free base forms and salt forms, the use of the salt form is in fact equivalent to the use of the base form. A list of suitable salts is found, for example, in s.m. berge et al, j.pharm.sci. [ journal of pharmaceutical science ],1977,66, pages 1-19, which are hereby incorporated by reference in their entirety.

"pharmaceutically acceptable acid addition salts" means those salts which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable and which are formed with inorganic acids (e.g., hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, nitric, phosphoric, and the like) and organic acids (e.g., acetic, trichloroacetic, trifluoroacetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic, benzoic, 2-acetoxybenzoic, butyric, camphoric, camphorsulfonic, cinnamic, citric, diglucosic, ethanesulfonic, glutamic, glycolic, glycerophosphoric, hemisulfuric, heptanoic, hexanoic, formic, fumaric, 2-hydroxyethanesulfonic (isethionic), lactic, maleic, hydroxymaleic, malic, malonic, mandelic, trimesylate, methanesulfonic, and the like), Naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.).

"pharmaceutically acceptable base addition salts" means those salts which retain the biological effectiveness and properties of the free acid and which are not biologically or otherwise undesirable and which are formed with inorganic bases such as ammonia or hydroxides, carbonates, or ammonium bicarbonates, or metal cations such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of: primary, secondary and tertiary amine compounds, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compound, tetraethylammonium compound, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine, dicyclohexylamine, dibenzylamine, aniline, n, N' -dibenzylethylenediamine, polyamine resins, and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

By "solvate" is meant a complex of variable stoichiometry formed by a solute (e.g., a compound of formula (I)) and a solvent (e.g., water, ethanol, or acetic acid). This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated (e.g., when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid). In general, such solvents, selected for the purposes of this disclosure, do not interfere with the biological activity of the solute. Solvates encompass both solution phases and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

By "hydrate" is meant a solvate wherein one or more solvent molecules is water.

The compounds of the present disclosure, as discussed below, include the free bases or acids thereof, salts, solvates, and prodrugs thereof, and may include oxidized sulfur atoms or quaternized nitrogen atoms (although not specifically illustrated or shown) in their structures, particularly in pharmaceutically acceptable forms thereof. Such forms (particularly pharmaceutically acceptable forms) are intended to be encompassed by the appended claims.

Isomer terminology and conventions

"isomers" means compounds having the same number and type of atoms, and thus the same molecular weight, but differing in the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.

"stereoisomer" or "optical isomer" means a stable isomer having at least one chiral atom or restricted rotation resulting in a plane of perpendicular asymmetry (e.g., certain biphenyl, allene, and spiro compounds) and which can rotate plane polarized light. Because asymmetric centers and other chemical structures are present in the compounds of the present disclosure that can lead to stereoisomerism, the present disclosure contemplates stereoisomers and mixtures thereof. The compounds of the present disclosure and salts thereof include asymmetric carbon atoms and thus may exist as individual stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as racemic mixtures. However, if desired, such compounds may be prepared or isolated as stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures of enriched stereoisomers. As discussed in more detail below, individual stereoisomers of the compounds are prepared by synthesis from optically active starting materials containing the desired chiral center, or by preparation of a mixture of enantiomeric products followed by separation or resolution (e.g., conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of enantiomers on chiral chromatographic columns). Starting compounds of a particular stereochemistry are either commercially available or are prepared by the methods described below and resolved by techniques well known in the art.

"enantiomers" means a pair of stereoisomers that are non-superimposable mirror images of each other.

"diastereomer" or "diastereomer" means optical isomers that do not form mirror images of each other.

"racemic mixture" or "racemate" means a mixture containing equal parts of a single enantiomer.

"non-racemic mixture" means a mixture containing unequal parts of individual enantiomers.

"geometric isomer" means a stable isomer resulting from rotational freedom constraints in double bonds (e.g., cis-2-butene and trans-2-butene) or ring structures (e.g., cis-1, 3-dichlorocyclobutane and trans-1, 3-dichlorocyclobutane). Because carbon-carbon bis (olefinic) bonds, C ═ N double bonds, ring structures, and the like may be present in the compounds of the present disclosure, the present disclosure contemplates each of the different stable geometric isomers and mixtures thereof resulting from the arrangement of substituents around the double bonds and in the ring structures. Substituents and isomers are represented using the cis/trans convention or using the E or Z system, where the term "E" means that the higher order substituents are on opposite sides of the double bond and the term "Z" means that the higher order substituents are on the same side of the double bond. A thorough discussion of E and Z isomerism is provided in: march, Advanced Organic Chemistry: Reactions, mechanics, and Structure [ Advanced Organic Chemistry: reactions, mechanisms and structures ]4 th edition, John Wiley&Sons [ John Willi parent-child publishing Co],1992，Which is hereby incorporated by reference in its entirety. Several of the examples below represent individual E isomers, individual Z isomers and mixtures of E/Z isomers. The determination of the E and Z isomers can be carried out by analytical methods, such as X-ray crystallography,¹H NMR, and¹³C NMR。

some compounds of the present disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the present disclosure include all such tautomers.

It is well known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including the type of activity exhibited, degree of activity, toxicity, etc.). Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare enantiomers of the compounds of the present disclosure from the knowledge of the present disclosure and prior art.

Thus, while racemic forms of the drug may be used, they are generally not as effective as administering an equivalent amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and act merely as a simple diluent. For example, although ibuprofen has previously been administered in the racemate, it has been found that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (however, in the case of ibuprofen, although the R-isomer is inactive, it is converted to the S-isomer in vivo and the racemic form of the drug therefore acts at a slower rate than the pure S-isomer). Furthermore, the pharmacological activity of enantiomers may have significantly different biological activities. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. Indeed, some purified enantiomers are more advantageous than racemates because purified individual isomers have been reported to have faster transdermal permeation rates than racemic mixtures. See U.S. patent nos. 5,114,946 and 4,818,541.

Thus, it would be therapeutically more beneficial to preferentially administer one enantiomer if it had a higher activity, lower toxicity, or more preferred in vivo distribution pharmacologically than the other enantiomer. In this way, the patient receiving treatment will be exposed to a lower total dose of drug and a lower dose of an enantiomer or other enantiomeric inhibitor that may be toxic.

The preparation of pure enantiomers or mixtures with the desired enantiomeric excess (ee) or enantiomeric purity can be accomplished by one or more of a number of methods known to those skilled in the art for (a) separation or resolution of enantiomers, or (b) enantioselective synthesis, or by a combination of such methods. These resolution methods typically rely on chiral recognition, including, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliary agents, enantioselective synthesis, enzymatic and non-enzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are generally disclosed in: chiral Separation Techniques A Practical Approach [ Chiral Separation technique: a practical method (2 nd edition), g.subramanian (editors), Wiley-VCH [ willi-VCH corporation ], 2000; beesley and r.p.w.scott, Chiral Chromatography [ Chiral Chromatography ], John Wiley & Sons [ John willi dad publishing company ], 1999; and Satinder Ahuja, Chiral Separations by Chromatography, am. chem. soc. [ proceedings of the american society of chemists ], 2000. Furthermore, there are equally well known methods for quantifying enantiomeric excess or purity (e.g. GC, HPLC, CE or NMR) and for identifying absolute configuration and conformation (e.g. CD ORD, X-ray crystallography, or NMR).

In general, all tautomeric forms and isomeric forms and mixtures of chemical structures or compounds, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, are contemplated unless the specific stereochemistry or isomeric form is specifically indicated in the compound name or structure.

Pharmaceutical administration and treatment terminology and conventions

A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

The term "pharmaceutically effective amount" or "therapeutically effective amount" or "effective amount" means an amount of a compound according to the present disclosure that, when administered to a patient in need thereof, is sufficient to effect treatment of a disease state, condition, or disorder in which the compound has utility. Such an amount is sufficient to elicit the biological or medical response of a tissue, system or patient sought by the researcher or clinician. The amount of a compound according to the present disclosure that constitutes a therapeutically effective amount will vary depending upon such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease state or disorder being treated and its severity, the drug being used in combination or with the compound of the present disclosure, and the age, weight, general health, sex, and diet of the patient. Such therapeutically effective amounts can be routinely determined by those of ordinary skill in the art based on their own knowledge, the prior art, and the present disclosure.

As used herein, the term "pharmaceutical composition" refers to a compound of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, in a form suitable for oral or parenteral administration, and at least one pharmaceutically acceptable carrier.

"carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ or body part of a subject to another organ or body part of the subject.

"combination" refers to a fixed combination in the form of a dosage unit, or administration in combination (where a compound of the present disclosure and at least one combination partner (e.g., another drug as explained below, also referred to as a "therapeutic agent" or "co-agent") may be administered independently at the same time or separately within time intervals, particularly where the time intervals allow the combination partners to exhibit the beneficial effect of the therapeutic agents working in concert). The beneficial effects of the combination include, but are not limited to, synergistic effects, e.g., synergy and/or pharmacokinetic or pharmacodynamic co-action, or any combination thereof, resulting from the combination of the therapeutic agents. In one embodiment, the combined administration of these therapeutic agents is performed over a defined period of time (e.g., minutes, hours, days, or weeks, depending on the combination selected). "

The individual components may be packaged in one kit or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to a desired dosage prior to administration. The terms "co-administration" or "combined administration" and the like as used herein are intended to encompass administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or simultaneously.

As used herein, the term "pharmaceutical combination" means a product resulting from the mixing or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents (e.g., the compounds and combination partners of the present disclosure) are administered to a patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that the therapeutic agents (e.g., a compound of the present disclosure and a combination partner) are administered to a patient as separate entities simultaneously, concurrently or sequentially (without specific time constraints), wherein such administration provides therapeutically effective levels of both compounds in the body of the patient. The latter is also applicable to cocktail therapies, such as the administration of three or more therapeutic agents.

A subject is "in need of" a treatment (preferably, a human) if such subject would benefit biologically, medically or in quality of life from such treatment.

The terms "PCSK 9" or "proprotein convertase subtilisin/kexin 9 type" refer interchangeably to subtilases belonging to the secretory type (the natural human proprotein convertase of the proteinase K subfamily of the family PCSK9 is synthesized as a lysogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum and is thought to function as a proprotein convertase PCSK9 functions in cholesterol homeostasis and possibly in cortical neuronal differentiation. mutations in the PCSK9 gene are responsible for autosomal dominant familial hypercholesterolemia. (Burnett and hoper, clin. biochem. rev. [ clinical biochemistry review ] (2008)29 (2008): 11-26)

As used herein, the term "inhibit (inhibition, or inhibiting)" refers to a reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

As used herein, the term "treating" of any disease or disorder refers to alleviating or alleviating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of its clinical symptoms); or ameliorating or improving at least one physical parameter or biomarker associated with the disease or disorder, including those physical parameters or biomarkers that may not be discernible by the patient.

As used herein, the term "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delay the onset or progression of the disease or disorder.

By "pharmaceutically acceptable" it is meant that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.

Unless otherwise indicated, "disorder" means the term disease, condition, or affliction, and is used interchangeably with these terms.

By "administering" is meant either directly administering the disclosed compound, or a pharmaceutically acceptable salt or composition of the disclosed compound, to a subject, or administering a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt of the compound or composition, to a subject, which results in an equivalent amount of the active compound in the subject.

By "prodrug" is meant a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to the disclosed compound.

"compounds of the present disclosure", "compounds of the present disclosure" and equivalent expressions (unless otherwise specifically indicated) refer to compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), and (Io) as described herein, including tautomers, prodrugs, salts (particularly pharmaceutically acceptable salts), and solvates and hydrates thereof, as the context allows, as well as all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium ("D") substitutions), as well as inherently formed moieties (e.g., polymorphs, solvates, and/or hydrates). For the purposes of this disclosure, solvates and hydrates are generally considered compositions. In general and preferably, the compounds of the present disclosure and the formulae representing the compounds of the present disclosure are understood to include only stable compounds thereof and to exclude unstable compounds, even though unstable compounds may be considered to be actually included in the formula of the compounds. Similarly, where the context permits, references to intermediates (whether or not they are themselves claimed) are intended to include their salts and solvates. For clarity, certain circumstances are sometimes indicated in the text where context allows, but these are purely illustrative and are not intended to exclude other circumstances where context allows.

"intermediates of the present disclosure", "disclosed intermediates", and equivalent expressions (unless specifically indicated otherwise) refer to compounds having formulae (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), and (IIIj), as described herein, including tautomers, prodrugs, salts (particularly pharmaceutically acceptable salts), and solvates and hydrates thereof, as the context permits, as well as all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium ("D") substitutions), as well as inherently formed moieties (e.g., polymorphs, solvates, and/or hydrates). For the purposes of this disclosure, solvates and hydrates are generally considered compositions. In general and preferably, intermediates of the present disclosure and formulae representing intermediates of the present disclosure are understood to include only stable compounds thereof and to exclude unstable compounds, even though unstable compounds may be considered to be actually included in the formula of compounds. Similarly, where the context permits, references to intermediates (whether or not they are themselves claimed) are intended to include their salts and solvates. For clarity, certain circumstances are sometimes indicated in the text where context allows, but these are purely illustrative and are not intended to exclude other circumstances where context allows.

By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic or diagnostic agent. For example, compounds having a "dangling valence" or carbanion are not contemplated compounds of the present disclosure.

In particular embodiments, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

As used herein, a "modulator of PCSK 9" refers to a compound or molecule capable of modulating PCSK9 biological activity or function and/or one or more downstream pathways mediated by PCSK9 activity.

As used herein, a "PCSK 9 inhibitor" refers to a compound or molecule capable of inhibiting PCSK9 biological activity or function and/or one or more downstream pathways mediated by PCSK9 signaling. Inhibitors of PCSK9 activity include compounds that block, antagonize, inhibit or reduce (to any extent, including significantly) PCSK9 biological activity, including downstream pathways mediated by PCSK9 activity.

As used herein, terms such as "disorder or disease responsive to inhibition of PCSK 9", "disorder or condition responsive to inhibition of PCSK 9", "disorder or condition responsive to inhibition of PCSK9 activity", "disorder responsive to inhibition of PCSK 9", "disorder responsive to inhibition of PCSK9 activity", "disorder in which PCSK9 plays a role" include hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease (including aortic disease and cerebrovascular disease), peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis and xanthoma.

As used herein, "inhibiting PCSK9 activity" or "inhibiting PCSK 9" refers to a reduction in PCSK9 activity, e.g., by administering a compound of the invention.

The term "hypercholesterolemia" or "dyslipidemia" includes, for example, familial and non-familial hypercholesterolemia. Familial Hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by elevated serum cholesterol associated with Low Density Lipoprotein (LDL). Familial hypercholesterolemia includes heterozygous FH and homozygous FH. Hypercholesterolemia (or dyslipidemia) is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (elevated blood lipid levels) and hyperlipoproteinemia (elevated blood lipoprotein levels).

Hyperlipidemia is an increase in blood lipids. These lipids include cholesterol, cholesterol esters, phospholipids and triglycerides. Hyperlipidemia includes, for example, type I, type IIa, type IIb, type III, type IV and type V.

Hypertriglyceridemia is indicative of high triglyceride levels in the blood. Elevated triglyceride levels are associated with atherosclerosis (even in the absence of hypercholesterolemia) and are susceptible to cardiovascular disease.

"sitosterolemia" or "phytosterolemia" is a rare autosomal recessive inherited disorder of lipid metabolism characterized by excessive absorption of sitosterols in the gastrointestinal tract and decreased biliary excretion of dietary sterols (i.e., leading to the premature development of hypercholesterolemia, sarcoidosis, and xanthoma, atherosclerosis) as well as altered cholesterol synthesis.

"atherosclerosis" includes arteriosclerosis associated with the deposition of fatty substances, cholesterol, cellular waste, calcium and fibrin in the inner wall of arteries. The resulting accumulation is called plaque.

"atherosclerosis" or "atherosclerotic vascular disease (ASVD)" is a particular form of arteriosclerosis that involves the thickening, stiffening and loss of elasticity of the arterial wall due to the invasion and accumulation of leukocytes, including living, active leukocytes (producing inflammation) and residues of dead cells, including cholesterol and triglycerides. Thus, atherosclerosis is a syndrome affecting arterial blood vessels due to the chronic inflammatory response of leukocytes in the arterial wall.

"coronary heart disease," also known as atherosclerotic heart disease, atherosclerotic cardiovascular disease, coronary heart disease or ischemic heart disease, is the most common cause of heart disease types and heart attacks. The disease is caused by plaque accumulating along the inner wall of the arteries of the heart, which narrows the lumen of the artery and reduces blood flow to the heart.

"xanthoma" is a skin manifestation of lipid hyperplasia in which lipids accumulate in large foam cells within the skin. Xanthoma is associated with hyperlipidemia.

As used herein, the term "elevated concentration of lp (a)" refers to a serum lp (a) concentration above 30mg/dl (75 nmol/L). By "elevated serum lp (a)" is meant a level of serum lp (a) greater than about 14 mg/dL. In certain embodiments, a patient is considered to have elevated serum lp a) if the patient's measured serum lp (a) level is greater than about 15mg/dL, about 20mg/dL, about 25mg/dL, about 30mg/dL, about 35mg/dL, about 40mg/dL, about 45mg/dL, about 50mg/dL, about 60mg/dL, about 70mg/dL, about 80mg/dL, about 90mg/dL, about 100mg/dL, about 20mg/dL, about 140mg/dL, about 150mg dL, about 180mg/dL, or about 200mg/dL, and the patient's serum lp (a) level can be checked after a meal. In some embodiments, lp (a) levels are measured after a period of fasting (e.g., after 8 hours, 10 hours, 12 hours, or more of fasting). Exemplary methods of measuring patient serum lp (a) include, but are not limited to, rate immunoturbidimetry, ELISA, turbidimetry, immunoturbidimetry, and dissociation-enhanced lanthanide fluorescence immunoassay, although any clinically acceptable diagnostic method can be used in the context of the present disclosure.

"elevated triglyceride levels" or "ETL" refers to triglyceride levels to any degree that is determined to be undesirable or to be subject to targeted modulation.

"sepsis" is a systemic reaction characterized by arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, shortness of breath, and organ dysfunction. Sepsis can result from sepsis (i.e., an organism, its metabolic end products or toxins in the blood), including bacteremia (i.e., bacteria in the blood) and toxemia (i.e., toxins in the blood), including endotoxemia (i.e., endotoxins in the blood) the term "sepsis" also includes fungemia (i.e., fungi in the blood), viremia (i.e., viruses or viral particles in the blood) and parasitemia (i.e., helminths or protozoan parasites in the blood) thus sepsis and septic shock (acute circulatory failure due to sepsis, often associated with multiple organ failure and high mortality) can be caused by many organisms.

Specific examples of compounds having formula (I)

The present disclosure relates to compounds capable of modulating PCSK9, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof (useful for treating diseases and disorders associated with modulation of PCSK9 protein or enzymes). In another embodiment, the disclosure relates to compounds capable of inhibiting PCSK9 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof (useful for treating diseases and disorders associated with the inhibition of PCSK9 proteins or enzymes). The disclosure further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof (useful for inhibiting PCSK 9).

In one embodiment, the compound having formula (I) has the structure: formula (Ia):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides and tautomers thereof.

In another embodiment, the compound having formula (I) has the structure: formula (Ib):

In another embodiment, the compound having formula (I) has the structure: formula (Ic):

In another embodiment, the compound having formula (I) has the structure: formula (Id):

In another embodiment, the compound having formula (I) has the structure: formula (Ie):

In another embodiment, the compound having formula (I) has the structure: formula (If):

In another embodiment, the compound having formula (I) has the structure: formula (Ig):

In another embodiment, the compound having formula (I) has the structure: formula (Ih):

In another embodiment, the compound having formula (I) has the structure: formula (Ii):

In another embodiment, the compound having formula (I) has the structure: formula (Ij):

wherein x is 0, 1, or 2; and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, N-oxides and tautomers thereof.

In another embodiment, the compound having formula (I) has the structure: formula (Ik):

In another embodiment, the compound having formula (I) has the structure: formula (Im):

In another embodiment, the compound having formula (I) has the structure: formula (Io):

In some embodiments of the above formula (e.g., formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii): formula (Ij), formula (Ik), formula (Im), and/or formula (Io)),

X₃is-CH₂- (when X)₁And X₂Each independently is H or (C) ₁-C₆) Alkyl, or X₁And X₂Together with the carbon atom to which they are attached form ═ (O), or X₃is-O-, -NH-or-N (C)₁-C₆) Alkyl- (when X)₁And X₂When taken together with the carbon atom to which they are attached to form ═ (O);

R₁is (C)₆-C₁₀) Aryl OR 5-OR 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are-OR₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one to four R₁₁Substitution;

R₂is H, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) Carbocyclyl group, (C)₃-C₇) Cycloalkenyl, 5-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, (C)₆-C₁₀) Aryl, or a 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the alkyl is optionally substituted with one to four R₁₈And said carbocyclyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R₁₉Substitution;

R₃is H, D, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, or (C)₁-C₆) Hydroxyalkyl, wherein the alkyl is optionally substituted with one to four R₁₄Substitution;

R₄is H or (C)₁-C₆) An alkyl group; or

R₅And R₇Each independently H, D, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, or (C)₁-C₆) Hydroxyalkyl group wherein said (C)₁-C₆) Alkyl is optionally substituted with one to four D;

R₆is (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, or (C)₁-C₆) Hydroxyalkyl, wherein the alkyl is optionally substituted with one to four substituents each independently selected from the group consisting of: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group;

R₈is H, (C)₁-C₆) Alkyl, or (C)₁-C₆) Haloalkyl, wherein the alkyl is optionally substituted with one to four substituents each independently selected from: (C)₃-C₇) Carbocyclyl, 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, -NR₁₆R₁₇and-C (O) NR₁₆R₁₇；

R₁₀is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one to four R₂₂Substitution;

R₁₂And R₁₃Each independently is H or (C)₁-C₆) An alkyl group;

each R₁₄D, NR independently at each occurrence₁₅R_15'、(C₃-C₇) A carbocyclyl, or a 3-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said carbocyclyl and heterocyclyl are optionally substituted with one to four substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, and (C)₁-C₆) A haloalkoxy group;

R₁₅and R_15’Each independently is H or (C)₁-C₆) An alkyl group;

R₁₆and R₁₇Each independently is H or (C)₁-C₆) Alkyl, or

each R₁₈Independently at each occurrence is (C)₃-C₇) Carbocyclyl, 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R₂₀Substitution;

Two R₁₉When on adjacent atoms form together (C) ₆-C₁₀) Aryl or a 5-or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted with one to four substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH and CN;

R₂₁is H or (C)₁-C₆) An alkyl group;

each R₂₂Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, CN, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one to four R₂₃Substitution;

each R₂₃Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -CH₂(OCH₂CH₂)_1-3OCH₂CH₃-OH, CN, or a 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl is optionally substituted with one to four substituents each independently selected from halogen, (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to four substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂) (ii) a And is

In some embodiments having the formula above, X₁And X₂Each independently is H or (C)₁-C₆) Alkyl, or X₁And X₂Together with the carbon atom to which they are attached form ═ (O);

R₁is (C)₆-C₁₀) Aryl OR 5-OR 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are-OR ₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one to four R₁₁Substitution;

R₄is H or (C)₁-C₆) An alkyl group; or

R₆is (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, or (C)₁-C₆) Hydroxyalkyl, wherein the alkyl is optionally substituted with one to four substituents each independently selected from the group consisting of: (C) ₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group;

R₁₂and R₁₃Each independently is H or (C)₁-C₆) An alkyl group;

each R₁₄D, NR independently at each occurrence₁₅R_15'、(C₃-C₇) A carbocyclyl, or a 3-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, whereinSaid carbocyclyl and heterocyclyl are optionally substituted with one to four substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, and (C)₁-C₆) A haloalkoxy group;

R₁₅And R_15’Each independently is H or (C)₁-C₆) An alkyl group;

R₁₆and R₁₇Each independently is H or (C)₁-C₆) Alkyl, or

Two R₁₉When on adjacent atoms form together (C)₆-C₁₀) Aryl or a 5-or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted with one to four substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH and CN;

each R₂₀Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C) ₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, oxo, -OH, or CN; or

R₂₁is H or (C)₁-C₆) An alkyl group;

each R₂₃Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -CH₂(OCH₂CH₂)_1-3OCH₂CH₃-OH, CN, or a 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl is optionally substituted with one to four substituents each independently selected from halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to four substituents each independently selected from: halogen, (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂) (ii) a And is

In some embodiments having the formula above, X₁Is H or (C)₁-C₆) An alkyl group. In another embodiment X₁Is H. In yet another embodiment, X₁Is (C)₁-C₆) An alkyl group.

In some embodiments having the formula above, X₂Is H or (C)₁-C₆) An alkyl group. In another embodiment X₂Is H. In yet another embodiment, X₂Is (C)₁-C₆) An alkyl group.

In some embodiments having the formula above, X₁And X₂Together with the carbon atom to which they are attached form ═ (O).

In some embodiments having the formula above, X₁Is H and X₂Is H. In another embodiment, X₁Is H and X₂Is (C)₁-C₆) An alkyl group. In yet another embodiment, X₁Is (C)₁-C₆) Alkyl and X₂Is (C)₁-C₆) An alkyl group.

In some embodiments having the above formula, when X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-O-, -NH-or-N (C)₁-C₆) An alkyl group-. In another embodiment, when X ₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-N (C)₁-C₆) An alkyl group-. In yet another embodiment, when X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-O-. In another embodiment, when X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-NH-. In yet another embodiment, when X₁And X₂Each independently is H or (C)₁-C₆) Alkyl, or X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-. In another embodiment, when X₁And X₂Each independently is H or (C)₁-C₆) When alkyl is present, X₃is-CH₂-. In yet another embodiment, when X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-。

In some embodiments having the formula above, R₁Is (C)₆-C₁₀) Aryl OR 5-OR 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are-OR₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In another embodiment, R₁Is phenyl OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one to three R ₁₁And (4) substitution. In yet another embodiment, R₁Is (C)₆-C₁₀) Aryl, OR 5-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are-OR₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In another embodiment, R₁Is phenyl OR a 5-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution.

In yet another embodiment, R₁Is (C)₆-C₁₀) Aryl radicalsOR a 6 membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are-OR₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In another embodiment, R₁Is phenyl, OR 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl is-OR₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In another embodiment, R₁Is (C)₆-C₁₀) Aryl radicals, substituted by-OR₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In yet another embodiment, R₁Is phenyl, which is-OR₁₀or-NR₂₁R₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In another embodiment, R ₁Is (C)₆-C₁₀) Aryl radicals, substituted by-OR₁₀or-NR₂₁R₁₀Substituted and substituted with one to three R₁₁And (4) substitution. In yet another embodiment, R₁Is phenyl, which is-OR₁₀or-NR₂₁R₁₀Substituted and substituted with one to three R₁₁And (4) substitution.

In another embodiment, R₁Is (C)₆-C₁₀) Aryl radicals, substituted by-NR₂₁R₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In yet another embodiment, R₁Is phenyl, which is substituted by-NR₂₁R₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In another embodiment, R₁Is (C)₆-C₁₀) Aryl radicals, substituted by-NR₂₁R₁₀Substituted and substituted with one to three R₁₁And (4) substitution. In yet another embodiment, R₁Is phenyl, which is substituted by-NR₂₁R₁₀Substituted and substituted with one to three R₁₁And (4) substitution. In another embodiment, R₁Is (C)₆-C₁₀) Aryl radicals, substituted by-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In another embodiment, R₁Is phenyl, which is-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In yet another embodiment, R₁Is (C)₆-C₁₀) Aryl radicals, substituted by-OR₁₀Substituted and substituted with one to three R₁₁And (4) substitution. In another embodiment, R₁Is phenyl, which is-OR₁₀Substituted and substituted with one to three R₁₁And (4) substitution.

In some embodiments having the formula above, R₂Is H, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C) ₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) Carbocyclyl group, (C)₃-C₇) Cycloalkenyl, 5-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, (C)₆-C₁₀) Aryl, or a 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the alkyl is optionally substituted with one to three R₁₈Substituted and said carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R₁₉And (4) substitution. In another embodiment, R₂Is H, (C)₁-C₃) Alkyl, (C)₂-C₄) Alkenyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) Carbocyclyl group, (C)₃-C₇) Cycloalkenyl, 5-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, (C)₆-C₁₀) Aryl, or a 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the alkyl is optionally substituted with one to three R₁₈And said carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R₁₉And (4) substitution. In yet another embodiment, R₂Is H, (C)₁-C₃) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) Carbocyclyl, 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C)₆-C₁₀) Aryl, or a 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein theAlkyl is optionally substituted with one to three R₁₈And said carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R ₁₉And (4) substitution.

In another embodiment, R₂Is H, (C)₁-C₃) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to three R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉And (4) substitution. In another embodiment, R₂Is H, (C)₁-C₆) Alkyl, or-NR₁₂R₁₃Wherein said alkyl is optionally substituted with one to three R₁₈And (4) substitution. In another embodiment, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, or-NR₁₂R₁₃. In yet another embodiment, R₂Is H, (C)₁-C₃) Alkyl, (C)₁-C₆) Haloalkyl, (C)₃-C₇) Carbocyclyl, 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to three R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉And (4) substitution. In another embodiment, R₂Is (C)₁-C₃) Alkyl optionally substituted with one to three R₁₈And (4) substitution. In yet another embodiment, R₂Is (C)₁-C₃) Alkyl is substituted by one to three R₁₈And (4) substitution. In another embodiment, R₂Is (C)₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said carbocyclyl and heterocyclyl are optionally substituted with one to four R ₁₉And (4) substitution.

In another embodiment, R₂Is (C)₁-C₃) Alkyl, (C)₁-C₆) Haloalkyl, (C)₃-C₇) Carbocyclic radicals, or containing radicals selected fromN, O and S, wherein the alkyl group is optionally substituted with one to three R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉And (4) substitution. In another embodiment, R₂Is (C)₁-C₃) Alkyl, (C)₁-C₆) Haloalkyl, (C)₃-C₇) Carbocyclyl, 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein the alkyl is substituted with one to three R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉And (4) substitution.

In some embodiments having the formula above, R₃Is H, D, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy group, (C)₁-C₄) Haloalkyl, (C)₁-C₄) Haloalkoxy, or (C)₁-C₄) Hydroxyalkyl, wherein the alkyl is optionally substituted with one to three R₁₄And (4) substitution. In another embodiment, R₃Is H, D, (C)₁-C₄) Alkyl, (C)₁-C₄) Haloalkyl, or (C)₁-C₄) Hydroxyalkyl, wherein the alkyl is optionally substituted with one to three R₁₄And (4) substitution. In yet another embodiment, R₃Is H, D, (C)₁-C₄) Alkyl, or (C)₁-C₄) Haloalkyl wherein said alkyl is optionally substituted with one to three R₁₄And (4) substitution. In another embodiment, R ₃Is H, D or is optionally substituted with one to three R₁₄Substituted (C)₁-C₄) An alkyl group. In yet another embodiment, R₃Is H, D or is optionally substituted by one or two R₁₄Substituted (C)₁-C₄) An alkyl group. In another embodiment, R₃Is H or optionally substituted by one or two R₁₄Substituted (C)₁-C₄) An alkyl group. In yet another embodiment, R₃Is H. In another embodiment, R₃Is optionally substituted by one or two R₁₄Substituted (C)₁-C₄) An alkyl group. In yet another embodiment, R₃Is H or (C)₁-C₄) An alkyl group. In another embodiment, R₃Is (C)₁-C₄) An alkyl group.

In some embodiments having the formula above, R₄Is H or (C)₁-C₃) An alkyl group. In another embodiment, R₄Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₄Is H, methyl, ethyl, n-propyl or i-propyl. In another embodiment, R₄Is H, methyl or ethyl. In yet another embodiment, R₄Is H or methyl. In another embodiment, R₄Is H.

In some embodiments having the formula above, R₃And R₄Together with the atoms to which they are attached form a 5-or 6-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S. In another embodiment, R₃And R₄Together with the atoms to which they are attached form a 6-or 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S. In yet another embodiment, R ₃And R₄Together with the atoms to which they are attached form a 5-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S. In another embodiment, R₃And R₄Together with the atoms to which they are attached form a 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S. In yet another embodiment, R₃And R₄Together with the atoms to which they are attached form a 6 membered heterocyclyl ring comprising 1-3 heteroatoms selected from N, O and S.

In some embodiments having the formula above, R₅Is H, D, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, or (C)₁-C₃) Hydroxyalkyl group wherein said (C)₁-C₃) Alkyl is optionally substituted with one or more (i.e., one to seven) D. In another embodiment, R₅Is H, D, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) A hydroxyalkyl group,wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more D. In yet another embodiment, R₅Is H, D, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, or (C)₁-C₃) Hydroxyalkyl group wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more D. In another embodiment, R₅Is H, D, (C)₁-C₃) Alkyl, or (C)₁-C₃) Haloalkyl, wherein said (C) ₁-C₆) Alkyl is optionally substituted with one or more D. In yet another embodiment, R₅Is H, D or (C)₁-C₃) An alkyl group. In another embodiment, R₅Is H or (C)₁-C₃) An alkyl group. In yet another embodiment, R₅Is H or (C)₁-C₂) An alkyl group. In another embodiment, R₅Is H, methyl, or ethyl. In yet another embodiment, R₅Is H or methyl. In another embodiment, R₅Is H. In yet another embodiment, R₅Is methyl.

In some embodiments having the formula above, R₆Is (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, or (C)₁-C₃) Hydroxyalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH, and-C (O) O (C)₁-C₆) An alkyl group. In another embodiment, R₆Is (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, or (C)₁-C₃) Hydroxyalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of:(C₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -C (O) (C)₁-C₃) Alkyl, -C (O) OH and-C (O) O (C)₁-C₃) An alkyl group. In yet another embodiment, R ₆Is (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) Hydroxyalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -C (O) (C)₁-C₃) Alkyl, -C (O) OH and-C (O) O (C)₁-C₃) An alkyl group. In another embodiment, R₆Is (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, or (C)₁-C₃) Hydroxyalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -C (O) (C)₁-C₃) Alkyl, -C (O) OH and-C (O) O (C)₁-C₃) An alkyl group.

In another embodiment, R₆Is (C)₁-C₃) Alkyl, or (C)₁-C₃) Haloalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from: (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -C (O) (C)₁-C₃) Alkyl, -C (O) OH and-C (O) O (C)₁-C₃) An alkyl group. In yet another embodiment, R₆Is (C)₁-C₃) Alkyl optionally substituted with one to three substituents each independently selected from: (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -C (O) (C)₁-C₃) Alkyl, -C (O) OH and-C (O) O (C)₁-C₃) An alkyl group. In another embodiment, R₆Is (C)₁-C₃) An alkyl group which is substituted by one to three substituents each independently selected from Generation: (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -C (O) (C)₁-C₃) Alkyl, -C (O) OH and-C (O) O (C)₁-C₃) An alkyl group. In yet another embodiment, R₆Is (C)₁-C₃) Alkyl optionally substituted with one to three substituents each independently selected from: (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -C (O) (C)₁-C₃) Alkyl, and-C (O) OH. In another embodiment, R₆Is (C)₁-C₃) Alkyl substituted with one to three substituents each independently selected from the group consisting of: (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -C (O) (C)₁-C₃) Alkyl, and-C (O) OH.

In some embodiments having the formula above, R₇Is H, D, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, or (C)₁-C₃) Hydroxyalkyl group wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more D. In another embodiment, R₇Is H, D, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) Hydroxyalkyl group wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more D. In yet another embodiment, R₇Is H, D, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, or (C)₁-C₃) Hydroxyalkyl group wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more D. In another embodiment, R ₇Is H, D, (C)₁-C₃) Alkyl, or (C)₁-C₃) Haloalkyl, wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more D. In yet another embodiment, R₇Is H, D or (C)₁-C₃) An alkyl group. In another embodiment, R₇Is H or (C)₁-C₃) An alkyl group. In yet another embodiment, R₇Is H or (C)₁-C₂) An alkyl group. In another embodiment, R₇Is H, methyl, or ethyl. In yet another embodiment, R₇Is H or methyl. In another embodiment, R₇Is H. In yet another embodiment, R₇Is methyl.

In some embodiments having the formula above, R₈Is H, (C)₁-C₅) Alkyl, or (C)₁-C₅) Haloalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from: (C)₃-C₇) Carbocyclyl, 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, -NR₁₆R₁₇and-C (O) NR₁₆R₁₇. In another embodiment, R₈Is H, (C)₁-C₅) Alkyl, or (C)₁-C₅) Haloalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from: 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, -NR₁₆R₁₇and-C (O) NR₁₆R₁₇. In another embodiment, R₈Is H, (C)₁-C₅) Alkyl, or (C) ₁-C₅) Haloalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from: (C)₃-C₇) Carbocyclyl, 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, -NR₁₆R₁₇and-C (O) NR₁₆R₁₇. In another embodiment, R₈Is H, (C)₁-C₅) Alkyl, or (C)₁-C₅) Haloalkyl, wherein the alkyl is optionally substituted with one to three substituents each independently selected from: 5-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, -NR₁₆R₁₇and-C (O) NR₁₆R₁₇。

In the above formulaIn some embodiments, R₉Is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, -OH, or CN. In another embodiment, R₉Is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, -OH, or CN. In yet another embodiment, R₉Is halogen, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -OH, or CN. In another embodiment, R₉Is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) A haloalkoxy group. In yet another embodiment, R₉Is halogen, (C)₁-C₃) Alkyl, or (C)₁-C₃) A haloalkyl group. In another embodiment, R₉Is halogen or (C)₁-C₃) An alkyl group. In yet another embodiment, R ₉Is halogen or (C)₁-C₃) A haloalkyl group. In another embodiment, R₉Is a halogen. In yet another embodiment, R₉Is F, Cl or Br. In another embodiment, R₉Is F or Cl. In yet another embodiment, R₉Is F. In yet another embodiment, R₉Is Cl.

In some embodiments having the formula above, R₁₀Is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one to three R₂₂And (4) substitution. In another embodiment, R₁₀Is phenyl or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl and heteroaryl groups are optionally substituted with one to three R₂₂And (4) substitution. In yet another embodiment, R₁₀Is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are substituted with one to three R₂₂And (4) substitution. In another embodiment, R₁₀Is phenyl or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is substituted with one to three R₂₂And (4) substitution.

In another embodiment, R₁₀Is (C)₆-C₁₀) Aryl or 5-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted with one to three R ₂₂And (4) substitution. In another embodiment, R₁₀Is (C)₆-C₁₀) Aryl or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted with one to three R₂₂And (4) substitution. In yet another embodiment, R₁₀Is (C)₆-C₁₀) Aryl or 5-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are substituted with one to three R₂₂And (4) substitution. In another embodiment, R₁₀Is (C)₆-C₁₀) Aryl or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are substituted with one to three R₂₂And (4) substitution.

In another embodiment, R₁₀Is phenyl or a 5-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl and heteroaryl groups are optionally substituted with one to three R₂₂And (4) substitution. In yet another embodiment, R₁₀Is phenyl or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl and heteroaryl are optionally substituted with one to three R₂₂And (4) substitution. In another embodiment, R₁₀Is phenyl or a 5-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is substituted with one to three R₂₂And (4) substitution. In yet another embodiment, R₁₀Is phenyl or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl is substituted with one to three R ₂₂And (4) substitution.

In another embodiment, R₁₀Is (C)₆-C₁₀) Aryl optionally substituted with one to three R₂₂And (4) substitution. In another embodiment, R₁₀Is (C)₆-C₁₀) Aryl substituted by one to three R₂₂And (4) substitution. In another embodiment, R₁₀Is a 5-or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, optionally substituted with one to three R₂₂And (4) substitution. In yet another embodiment, R₁₀Is a 5-or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, which is substituted with one to three R₂₂And (4) substitution. In another embodiment, R₁₀Is a 5 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, optionally substituted with one to three R₂₂And (4) substitution. In yet another embodiment, R₁₀A 6 membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, optionally substituted with one to three R₂₂And (4) substitution. In another embodiment, R₁₀Is a 5 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, substituted with one to three R₂₂And (4) substitution. In yet another embodiment, R₁₀A 6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, substituted with one to three R₂₂And (4) substitution. In another embodiment, R₁₀Is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with one to three R ₂₂And (4) substitution. In yet another embodiment, R₁₀Is phenyl or pyridyl, wherein said phenyl or pyridyl is substituted with one to three R₂₂And (4) substitution.

In some embodiments having the formula above, each R₁₁Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, -OH, or CN. In another embodiment, each R₁₁Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) A haloalkoxy group. In yet another embodiment, each R₁₁Independently at each occurrence is halogen, -OH, or CN. In another embodiment, each R₁₁Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or (C)₁-C₃) A haloalkyl group. In another embodiment, each R₁₁Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy or (C)₁-C₃) A haloalkoxy group. In yet another embodiment, each R₁₁Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) A haloalkoxy group. In another embodiment, each R₁₁Independently at each occurrence, is halogen, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) A haloalkoxy group. In yet another embodiment, each R ₁₁Independently at each occurrence is halogen.

In some embodiments having the formula above, R₁₂Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₁₂Is H or (C)₁-C₃) An alkyl group. In yet another embodiment, R₁₂Is H. In another embodiment, R₁₂Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₁₂Is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R₁₂Is methyl or ethyl. In yet another embodiment, R₁₂Is methyl.

In some embodiments having the formula above, R₁₃Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₁₃Is H or (C)₁-C₃) An alkyl group. In yet another embodiment, R₁₃Is H. In another embodiment, R₁₃Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₁₃Is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R₁₃Is methyl or ethyl. In yet another embodiment, R₁₃Is methyl.

In some embodiments having the formula above, R₁₂Is H and R₁₃Is H. In another embodiment, R₁₂Is H and R₁₃Is (a)C₁-C₃) An alkyl group. In yet another embodiment, R₁₂Is (C)₁-C₃) Alkyl and R₁₃Is H. In another embodiment, R₁₂Is (C)₁-C₃) Alkyl and R₁₃Is (C)₁-C₃) An alkyl group. In yet another embodiment, R ₁₂Is methyl and R₁₃Is methyl.

In some embodiments having the formula above, each R₁₄Independently at each occurrence is D, -NR₁₅R_15'、(C₃-C₇) A carbocyclyl, or a 3-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, wherein said carbocyclyl and heterocyclyl are optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, and (C)₁-C₆) A haloalkoxy group. In another embodiment, each R₁₄Independently at each occurrence is D, -NR₁₅R_15'、(C₃-C₇) A carbocyclyl, or a 3-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, wherein said carbocyclyl and heterocyclyl are optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, and (C)₁-C₃) A haloalkoxy group. In yet another embodiment, each R₁₄Independently at each occurrence is-NR₁₅R_15'、(C₃-C₇) A carbocyclyl, or a 3-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, wherein said carbocyclyl and heterocyclyl are optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, and (C) ₁-C₃) A haloalkoxy group.

In another embodiment, each R₁₄Independently at each occurrenceis-NR₁₅R_15'Or (C)₃-C₇) Carbocyclyl (which is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, and (C)₁-C₃) Haloalkoxy). In yet another embodiment, each R₁₄Independently at each occurrence is-NR₁₅R_15'Or (C)₃-C₇) Carbocyclyl (which is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₃) Alkyl, and (C)₁-C₃) Haloalkyl). In another embodiment, each R₁₄Independently at each occurrence is-NR₁₅R_15'Or (C)₃-C₇) Carbocyclyl (which is optionally substituted with one to three (C)₁-C₃) Alkyl substituted).

In some embodiments having the formula above, R₁₅Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₁₅Is H or (C)₁-C₃) An alkyl group. In yet another embodiment, R₁₅Is H. In another embodiment, R₁₅Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₁₅Is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R₁₅Is methyl or ethyl. In yet another embodiment, R₁₅Is methyl.

In some embodiments having the formula above, R_15'Is H or (C)₁-C₆) An alkyl group. In another embodiment, R _15'Is H or (C)₁-C₃) An alkyl group. In yet another embodiment, R_15'Is H. In another embodiment, R_15'Is (C)₁-C₃) An alkyl group. In yet another embodiment, R_15'Is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R_15'Is methyl or ethyl. In yet another embodiment, R_15'Is methyl.

In having at leastIn some embodiments of the above formula, R₁₅Is H and R_15'Is H. In another embodiment, R₁₅Is H and R_15'Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₁₅Is (C)₁-C₃) Alkyl and R_15'Is H. In another embodiment, R₁₅Is (C)₁-C₃) Alkyl and R_15'Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₁₅Is methyl and R_15'Is methyl.

In some embodiments having the formula above, R₁₆Is H or (C)₁-C₃) An alkyl group. In another embodiment, R₁₆Is H. In another embodiment, R₁₆Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₁₆Is H, methyl, ethyl, n-propyl or i-propyl. In another embodiment, R₁₆Is methyl, ethyl, n-propyl or i-propyl. In yet another embodiment, R₁₆Is H, methyl or ethyl. In another embodiment, R₁₆Is methyl or ethyl. In yet another embodiment, R₁₆Is H or methyl. In another embodiment, R ₁₆Is methyl. In yet another embodiment, R₁₆Is H or (C)₁-C₃) An alkyl group; or R₁₆And R₁₇Together with the nitrogen atom to which they are attached form a 4-to 7-membered heterocyclyl ring containing 1-2 additional heteroatoms selected from N, O and S. In yet another embodiment, R₁₆Is H or (C)₁-C₃) An alkyl group; or R₁₆And R₁₇Together with the nitrogen atom to which they are attached form a 4-to 7-membered heterocyclyl ring optionally containing 1-2 additional heteroatoms selected from N, O and S.

In some embodiments having the formula above, R₁₇Is H or (C)₁-C₃) An alkyl group. In another embodiment, R₁₇Is H. In another embodiment, R₁₇Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₁₇Is H, methyl, ethyl, n-propylOr i-propyl. In another embodiment, R₁₇Is methyl, ethyl, n-propyl or i-propyl. In yet another embodiment, R₁₇Is H, methyl or ethyl. In another embodiment, R₁₇Is methyl or ethyl. In yet another embodiment, R₁₇Is H or methyl. In another embodiment, R₁₇Is methyl.

In some embodiments having the formula above, R₁₆And R₁₇Together with the nitrogen atom to which they are attached form a 4-to 7-membered heterocyclyl ring containing 1-2 additional heteroatoms selected from N, O and S. In another embodiment, R ₁₆And R₁₇Together with the nitrogen atom to which they are attached form a 4-to 6-membered heterocyclyl ring containing 1-2 additional heteroatoms selected from N, O and S. In yet another embodiment, R₁₆And R₁₇Together with the nitrogen atom to which they are attached form a 4-or 5-membered heterocyclyl ring containing 1-2 additional heteroatoms selected from N, O and S.

In some embodiments having the formula above, R₁₆And R₁₇Together with the nitrogen atom to which they are attached form a 4-to 7-membered heterocyclyl ring optionally containing 1-2 additional heteroatoms selected from N, O and S. In another embodiment, R₁₆And R₁₇Together with the nitrogen atom to which they are attached form a 4-to 6-membered heterocyclyl ring optionally containing 1-2 additional heteroatoms selected from N, O and S. In yet another embodiment, R₁₆And R₁₇Together with the nitrogen atom to which they are attached form a 4-or 5-membered heterocyclyl ring optionally containing 1-2 additional heteroatoms selected from N, O and S.

In some embodiments having the formula above, each R₁₈Independently at each occurrence is (C)₃-C₇) Carbocyclyl, 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R ₂₀And (4) substitution. In another embodiment, each R₁₈At each time of dischargeIs independently at present (C)₃-C₇) Carbocyclyl, or 5-to 7-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one to four R₂₀And (4) substitution. In yet another embodiment, each R₁₈Independently at each occurrence is (C)₃-C₇) Carbocyclyl, or (C)₆-C₁₀) Aryl, wherein said carbocyclyl and aryl are optionally substituted with one to four R₂₀And (4) substitution. In another embodiment, each R₁₈Independently at each occurrence, is a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or a 5-or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, wherein the heterocyclyl and heteroaryl are optionally substituted with one to four R₂₀And (4) substitution.

In another embodiment, each R₁₈Independently at each occurrence is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are substituted with one to three R₂₀And (4) substitution. In yet another embodiment, each R₁₈Independently at each occurrence is phenyl or a 5-or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is substituted with one to three R₂₀And (4) substitution. In another embodiment, each R ₁₈Independently at each occurrence is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one to three R₂₀And (4) substitution. In yet another embodiment, each R₁₈Independently at each occurrence is phenyl or a 5-or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, wherein the phenyl and heteroaryl groups are optionally substituted with one to three R₂₀And (4) substitution.

In some embodiments having the formula above, R₁₉Is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, -OH, or CN. In another embodiment, R₁₉Is halogen, (C)₁-C₃) Alkyl, aryl, heteroaryl, and heteroaryl,(C₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) A haloalkoxy group. In another embodiment, R₁₉Is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, -OH, or CN. In another embodiment, R₁₉Is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, or-OH. In another embodiment, R₁₉Is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, or CN. In another embodiment, R₁₉Is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C) ₁-C₃) Haloalkyl, -OH, or CN. In another embodiment, R₁₉Is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -OH, or CN. In another embodiment, R₁₉Is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, -OH, or CN. In another embodiment, R₁₉Is halogen, (C)₁-C₃) Alkyl, or (C)₁-C₃) A haloalkyl group. In another embodiment, R₁₉Is halogen or (C)₁-C₃) An alkyl group.

In some embodiments having the above formula, two R₁₉When on adjacent atoms form together (C)₆-C₁₀) Aryl or a 5-or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl are optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH and CN. In another embodiment, two R₁₉When on adjacent atoms form together (C)₆-C₁₀) Aryl optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH and CN. In yet another embodiment, two R ₁₉When on adjacent atoms, together form a 5-or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH and CN. In another embodiment, two R₁₉When on adjacent atoms, together form a phenyl or 5-or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl and heteroaryl are optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH and CN.

In another embodiment, two R₁₉When on adjacent atoms, together form a phenyl group, optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH and CN. In yet another embodiment, two R₁₉When on adjacent atoms, together form a 5-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, optionally substituted with one or more substituents each independently selected from: halogen, (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH and CN. In another embodiment, two R₁₉When on adjacent atoms, together form a 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S, optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH and CN.

In some embodiments having the formula above, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, oxo, -OH, or CN. In another embodiment, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, oxo-OH, or CN. In yet another embodiment, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) A haloalkoxy group. In another embodiment, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, oxo, -OH, or CN. In yet another embodiment, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C) ₁-C₃) Alkoxy, -OH, or CN. In another embodiment, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -OH, or CN. In yet another embodiment, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) HalogenatedAn alkoxy group.

In another embodiment, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or (C)₁-C₃) A haloalkyl group. In yet another embodiment, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) An alkoxy group. In another embodiment, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy or (C)₁-C₃) A haloalkoxy group. In yet another embodiment, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or oxo. In another embodiment, each R₂₀Independently at each occurrence is halogen or (C)₁-C₃) An alkyl group. In yet another embodiment, each R₂₀Independently at each occurrence is (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, or (C)₁-C₃) A haloalkoxy group. In another embodiment, each R₂₀Independently at each occurrence is (C) ₁-C₃) Alkyl or (C)₁-C₃) A haloalkyl group.

In some embodiments having the formula above, each R₂₀Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or oxo; or when R is₁₈When it is carbocyclic or heterocyclic, two R₂₀When attached to the same carbon atom, together form ═ (O). In another embodiment, each R₂₀Independently at each occurrence is halogen or (C)₁-C₃) An alkyl group; or when R is₁₈When it is carbocyclic or heterocyclic, two R₂₀When attached to the same carbon atom, together form ═ (O).

In some embodiments having the above formula, when R₁₈When it is carbocyclic or heterocyclic, two R₂₀When attached to the same carbon atom, together form ═ (O). In another embodiment, when R₁₈Is carbonWhen cyclic, two R₂₀When attached to the same carbon atom, together form ═ (O). In another embodiment, when R₁₈When it is heterocyclic, two R₂₀When attached to the same carbon atom, together form ═ (O). In another embodiment, R₁₈Is substituted by one to three R₂₀Substituted carbocyclyl or heterocyclyl, and two R₂₀When attached to the same carbon atom, together form ═ (O). In another embodiment, R₁₈Is substituted by one to three R₂₀A substituted carbocyclyl, and two R₂₀When attached to the same carbon atom, together form ═ (O). In another embodiment, R ₁₈Is substituted by one to three R₂₀A substituted heterocyclic group, and two R₂₀When attached to the same carbon atom, together form ═ (O).

In some embodiments having the formula above, R₂₁Is H or (C)₁-C₃) An alkyl group. In another embodiment, R₂₁Is H. In another embodiment, R₂₁Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₂₁Is H, methyl, ethyl, n-propyl or i-propyl. In another embodiment, R₂₁Is methyl, ethyl, n-propyl or i-propyl. In yet another embodiment, R₂₁Is H, methyl or ethyl. In another embodiment, R₂₁Is methyl or ethyl. In yet another embodiment, R₂₁Is H or methyl. In another embodiment, R₂₁Is methyl.

In some embodiments having the formula above, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, -OH, CN, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one to three R₂₃And (4) substitution. In another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl group (a)C₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C) ₁-C₃) Haloalkoxy, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one to three R₂₃And (4) substitution. In yet another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, -OH, CN, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one to three R₂₃And (4) substitution. In another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, -OH, CN, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one to three R₂₃And (4) substitution.

In another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one to three R₂₃And (4) substitution. In yet another embodiment, each R₂₂Independently at each occurrence, is halogen, (C) ₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one to three R₂₃And (4) substitution. In another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₆-C₁₀) Aryl, or containing radicals selected from N, O and S1-3 heteroatoms of a 5-or 6-membered heteroaryl group, wherein the aryl and heteroaryl groups are optionally substituted with one to three R₂₃And (4) substitution. In yet another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or optionally substituted with one to three R₂₃Substituted (C)₆-C₁₀) And (4) an aryl group. In yet another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or 5-or 6-membered heteroaryl (optionally substituted with one to three R) comprising 1-3 heteroatoms selected from N, O and S₂₃Substitution). In another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or 5-or 6-membered heteroaryl (optionally substituted with one to three R) comprising 1-3 heteroatoms selected from N, O and S₂₃Substitution).

In another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or 5-membered heteroaryl (optionally substituted with one to three R) comprising 1-3 heteroatoms selected from N, O and S ₂₃Substitution). In yet another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or 6-membered heteroaryl (optionally substituted with one to three R) comprising 1-3 heteroatoms selected from N, O and S₂₃Substitution). In another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or 5-membered heteroaryl (substituted with one to three R) containing 1-3 heteroatoms selected from N, O and S₂₃Substitution). In yet another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or 6-membered heteroaryl (substituted with one to three R) containing 1-3 heteroatoms selected from N, O and S₂₃Substitution). In another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or optionally substituted with one to three R₂₃A substituted imidazolyl group. In yet another embodiment, each R₂₂Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, or by one to three R₂₃A substituted imidazolyl group.

In some embodiments having the formula above, each R₂₃Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, -CH₂(OCH₂CH₂)_1-3OCH₂CH₃-OH, CN, or a 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl is optionally substituted with one to three substituents each independently selected from halogen, (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂)。

In another embodiment, each R₂₃Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, -OH, CN, or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl is substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkane (I) and its preparation methodOxy, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: halogen, (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂)。

In another embodiment, each R₂₃Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, -CH₂(OCH₂CH₂)_1-3OCH₂CH₃-OH, CN, or a 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl is optionally substituted with one to three substituents each independently selected from halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂)。

In another embodiment, each R₂₃Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Haloalkyl, -OH, CN, or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl is optionally substituted with one to three substituents each independently selected from: halogen, (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂)。

In another embodiment, each R₂₃Independently at each occurrence, is halogen, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkyl, (C)₁-C₃) Haloalkoxy, or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: halogen, (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂)。

In another embodiment, each R₂₃Independently at each occurrence, is halogen, (C)₁-C₃) An alkyl group, or a 4-to 7-membered heterocyclyl group comprising 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl group is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂). In yet another embodiment, each R₂₃Independently at each occurrence is (C)₁-C₃) Alkyl or a 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl is optionally substitutedIs substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C) ₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂)。

In another embodiment, each R₂₃Independently at each occurrence is (C)₁-C₃) An alkyl group or a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl group is substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C) ₁-C₆) Alkyl radical)₂). In yet another embodiment, each R₂₃Independently at each occurrence is (C)₁-C₃) An alkyl group or a 4-to 7-membered heterocyclyl group comprising 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl group is optionally substituted with one to three substituents each independently selected from: (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂)。

In another embodiment, each R₂₃Independently at each occurrence is (C)₁-C₃) An alkyl group or a 4-to 7-membered heterocyclyl group comprising 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl group is optionally substituted with one to three substituents each independently selected from: (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: (C) ₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂). In yet another embodiment, each R₂₃At each occurrence independently is(C₁-C₃) An alkyl group or a 4-to 7-membered heterocyclyl group comprising 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl group is optionally substituted with one to three substituents each independently selected from: (C)₁-C₆) Alkyl, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: (C)₁-C₆) Alkyl, -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂)。

In another embodiment, each R₂₃Independently at each occurrence is (C)₁-C₃) Alkyl or a 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl is optionally substituted with one to three (C)₁-C₆) Alkyl substituted and optionally-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: -OH, -NH₂、-NH(C₁-C₆) Alkyl, and-N ((C)₁-C₆) Alkyl radical)₂). In yet another embodiment, each R ₂₃Independently at each occurrence is (C)₁-C₃) Alkyl or a 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S (wherein the heterocyclyl is optionally substituted with one to three (C)₁-C₆) Alkyl substituted and optionally-NR₂₄R₂₅Substituted) or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S (which is optionally substituted with one to three substituents each independently selected from: -OH, and-N ((C)₁-C₆) Alkyl radical)₂)。

In some embodiments having the formula above, R₂₄Is H, (C)₁-C₃) Alkyl, or optionally substituted by oneTo two (C)₁-C₆) Alkyl substituted (C)₃-C₇) A carbocyclic group. In another embodiment, R₂₄Is H, (C)₁-C₃) Alkyl, or optionally substituted by one to two (C)₁-C₃) Alkyl substituted (C)₃-C₇) A carbocyclic group. In another embodiment, R₂₄Is H, (C)₁-C₃) Alkyl, or (C)₃-C₇) A carbocyclic group. In another embodiment, R₂₄Is H, (C)₁-C₃) Alkyl, or (C)₃-C₅) A carbocyclic group. In yet another embodiment, R₂₄Is H or (C)₁-C₃) An alkyl group. In another embodiment, R₂₄Is H. In another embodiment, R₂₄Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₂₄Is (C)₃-C₅) Carbocyclyl optionally substituted with one to two (C)₁-C₆) Alkyl substitution. In yet another embodiment, R₂₄Is (C)₃-C₅) A carbocyclic group. In another embodiment, R ₂₄Is H, methyl, ethyl, n-propyl or i-propyl. In yet another embodiment, R₂₄Is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R₂₄Is H, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein said cyclopropyl, cyclobutyl and cyclopentyl are optionally substituted by one to two (C)₁-C₃) Alkyl substitution. In yet another embodiment, R₂₄Is H, methyl, ethyl, cyclopropyl or cyclobutyl, wherein said cyclopropyl and cyclobutyl are optionally substituted by one to two (C)₁-C₃) Alkyl substitution. In another embodiment, R₂₄Is H, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl. In yet another embodiment, R₂₄Is H, methyl, ethyl, cyclopropyl or cyclobutyl. In another embodiment, R₂₄Is H, methyl or ethyl. In another embodiment, R₂₄Is methyl or ethyl. In yet another embodiment, R₂₄Is H or methyl. In another embodiment, R₂₄Is methyl.

In some embodiments having the formula above, R₂₅Is H, (C)₁-C₃) Alkyl, or optionally substituted by one to two (C)₁-C₆) Alkyl substituted (C)₃-C₇) A carbocyclic group. In another embodiment, R₂₅Is H, (C)₁-C₃) Alkyl, or optionally substituted by one to two (C) ₁-C₃) Alkyl substituted (C)₃-C₇) A carbocyclic group. In another embodiment, R₂₅Is H, (C)₁-C₃) Alkyl, or (C)₃-C₇) A carbocyclic group. In another embodiment, R₂₅Is H, (C)₁-C₃) Alkyl, or (C)₃-C₅) A carbocyclic group. In yet another embodiment, R₂₅Is H or (C)₁-C₃) An alkyl group. In another embodiment, R₂₅Is H. In another embodiment, R₂₅Is (C)₁-C₃) An alkyl group. In yet another embodiment, R₂₅Is (C)₃-C₅) Carbocyclyl optionally substituted with one to two (C)₁-C₆) Alkyl substitution. In yet another embodiment, R₂₅Is (C)₃-C₅) A carbocyclic group. In another embodiment, R₂₅Is H, methyl, ethyl, n-propyl or i-propyl. In yet another embodiment, R₂₅Is methyl, ethyl, n-propyl or i-propyl. In another embodiment, R₂₅Is H, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein said cyclopropyl, cyclobutyl and cyclopentyl are optionally substituted by one to two (C)₁-C₃) Alkyl substitution. In yet another embodiment, R₂₅Is H, methyl, ethyl, cyclopropyl or cyclobutyl, wherein said cyclopropyl and cyclobutyl are optionally substituted by one to two (C)₁-C₃) Alkyl substitution. In another embodiment, R₂₅Is H, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl. In yet another embodiment, R ₂₅Is H, methyl, ethyl, cyclopropyl or cyclobutyl. In another embodiment, R₂₅Is H, methyl or ethyl. In another embodiment, R₂₅Is methyl or ethyl. In yet another embodiment, R₂₅Is H or methyl. In another embodiment, R₂₅Is methyl.

In some embodiments having the formula above, R₄Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl and R₅Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is H or (C)₁-C₆) Alkyl, and R₇Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is H or (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is H or (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₄Is H and R₅Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H, R₅Is H or (C)₁-C₆) Alkyl, and R₇Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H, R₅Is H or (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H, R₅Is H or (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R ₉Is chlorine.

In some embodiments having the formula above, R₄Is H or (C)₁-C₆) Alkyl and R₅Is (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is (C)₁-C₆) Alkyl, and R₇Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₄Is H and R₅Is (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H, R₅Is (C)₁-C₆) Alkyl, and R₇Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H, R₅Is (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H, R₅Is (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is chlorine.

In some embodiments having the formula above, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is H or (C)₁-C₆) Alkyl, and R₇Is (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is H or (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is H or (C)₁-C₆) Alkyl radical, R ₇Is (C)₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₄Is H, R₅Is H or (C)₁-C₆) Alkyl, and R₇Is (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H, R₅Is H or (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H, R₅Is H or (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is chlorine.

In some embodiments having the formula above, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is (C)₁-C₆) Alkyl, and R₇Is (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₄Is H, R₅Is (C)₁-C₆) Alkyl, and R₇Is (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H, R₅Is (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H, R₅Is (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is chlorine.

In some embodiments having the formula above, R₅Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₅Is H or (C)₁-C₆) Alkyl and R₇Is H or (C)₁-C₆) An alkyl group. In another embodiment, R ₅Is H or (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) An alkyl group, a carboxyl group,and R is₉Is a halogen. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is H or (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is chlorine.

In some embodiments having the formula above, R₅Is (C)₁-C₆) An alkyl group. In another embodiment, R₅Is (C)₁-C₆) Alkyl and R₇Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₅Is (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₅Is (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₅Is H or (C)₁-C₆) Alkyl and R₇Is (C)₁-C₆) An alkyl group. In another embodiment, R₅Is H or (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is a halogen.

In another embodiment, R₅Is H or (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₅Is (C)₁-C₆) Alkyl and R₇Is (C)₁-C₆) An alkyl group. In another embodiment, R₅Is (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₅Is (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is chlorine.

In some embodiments having the formula above, R₄Is H or (C)₁-C₆) Alkyl and R₇Is H or (C) ₁-C₆) An alkyl group.In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₄Is H and R₇Is H or (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H, R₇Is H or (C)₁-C₆) Alkyl, and R₉Is chlorine. In some embodiments having the formula above, R₄Is H or (C)₁-C₆) Alkyl and R₇Is (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₇Is (C)₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₄Is H and R₇Is (C)₁-C₆) An alkyl group. In another embodiment, R₄Is H, R₇Is (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H, R₇Is (C)₁-C₆) Alkyl, and R₉Is chlorine.

In some embodiments having the formula above, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is H or (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is H or (C) ₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₄Is H, R₅Is H or (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H, R₅Is H or (C)₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl radical, R₅Is (C)₁-C₆) Alkyl, and R₉Is chlorine. In another embodiment, R₄Is H, R₅Is (C)₁-C₆) Alkyl, and R₉Is a halogen. In another embodiment, R₄Is H, R₅Is (C)₁-C₆) Alkyl, and R₉Is chlorine.

In some embodiments having the formula above, R₄Is H or (C)₁-C₆) Alkyl and R₉Is a halogen. In another embodiment, R₄Is H or (C)₁-C₆) Alkyl and R₉Is chlorine. In another embodiment, R₄Is H and R₉Is a halogen. In another embodiment, R₄Is H and R₉Is chlorine. In another embodiment, R₅Is H or (C)₁-C₆) Alkyl and R₉Is a halogen. In another embodiment, R₅Is H or (C)₁-C₆) Alkyl and R₉Is chlorine. In another embodiment, R₅Is (C)₁-C₆) Alkyl and R₉Is a halogen. In another embodiment, R₅Is (C)₁-C₆) Alkyl and R₉Is chlorine. In another embodiment, R₇Is H or (C) ₁-C₆) Alkyl and R₉Is a halogen. In another embodiment, R₇Is H or (C)₁-C₆) Alkyl and R₉Is chlorine. In another embodiment, R₇Is (C)₁-C₆) Alkyl and R₉Is a halogen. In another embodiment, R₇Is (C)₁-C₆) Alkyl and R₉Is chlorine.

In some embodiments having the formula above, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), and X₃is-CH₂-. In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-, and R₉Is Cl. In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, and R₄Is H. In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, and R₇Is H. In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, and R₅Is H or (C)₁-C₄) An alkyl group. In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl, and R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR ₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution.

In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, and R₅Is H or (C)₁-C₄) An alkyl group. In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl, and R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Is substituted, and R₂Is H, (C)₁-C₆) Alkyl, -NR₁₂R₁₃、(C₁-C₆) Haloalkyl, (C)₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R ₁₉And (4) substitution.

In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Is substituted, and R₃Is H, (C)₁-C₆) Alkyl halidesOr optionally substituted by one to three R₁₄Substituted (C)₁-C₆) An alkyl group. In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R ₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) Alkyl, and R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group.

In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) Alkyl radical, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C) ₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl, and R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇。

In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Alkyl halidesOr optionally substituted by one to three more R₁₄Substituted (C)₁-C₆) Alkyl radical, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C) ₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl radical, R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇And R is₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R₂₂And (4) substitution.

In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, and R₅Is H or methyl. In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, and R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, R ₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Is substituted, and R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉And (4) substitution.

In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Is substituted, and R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R ₁₄Substituted (C)₁-C₆) An alkyl group. In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S,wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) Alkyl, and R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group.

In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR ₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) Alkyl radical, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl, and R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇。

In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR ₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) Alkyl radical, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl radical, R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇And R is₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substitutedGround is one to three R₂₂Is substituted, and R₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R ₂₂And (4) substitution.

In some embodiments having the formula above, X₁Is H and X₂Is H and X₃is-CH₂-. In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-, and R₉Is Cl. In another embodiment, X₁Is H and X₂Is H, R₉Is Cl, and R₄Is H. In yet another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, and R₇Is H. In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, and R₅Is H or (C)₁-C₄) An alkyl group. In yet another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl, and R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Is substituted, and R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR ₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉And (4) substitution.

In yet another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Is substituted, and R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) An alkyl group. In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR ₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) Alkyl, and R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group.

In yet another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R ₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) Alkyl radical, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl, and R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇。

In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R ₁₄Substituted (C)₁-C₆) Alkyl radical, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl radical, R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇，R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇And R is₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R₂₂Is substituted, and R₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R₂₂And (4) substitution.

In some embodiments having the formula above, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, and R₅Is H or methyl. In another embodiment, X ₁Is H and X₂Is H, R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, and R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In yet another embodiment, X₁Is H and X₂Is H, R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Is substituted, and R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉And (4) substitution.

In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, R₁Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S,wherein said phenyl OR heteroaryl is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C) ₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Is substituted, and R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) An alkyl group. In yet another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or (C)₁-C₆) Alkyl is optionally substituted with one to three R₁₄Is substituted, and R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C) ₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group.

In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) Alkyl radical, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl, and R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR ₁₆R₁₇。

In yet another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₄Is H, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkyl halidesRadical, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₃Is H, (C)₁-C₆) Haloalkyl, or optionally substituted with one to three R₁₄Substituted (C)₁-C₆) Alkyl radical, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl radical, R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇And R is₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R ₂₂Is substituted, and R₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R₂₂And (4) substitution.

In some embodiments having the formula above, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, and R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S. In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a group comprising,A 5-to 7-membered heterocyclyl ring of 1-3 heteroatoms of O and S, and R₇Is H. In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, and R₅Is H or (C)₁-C₄) An alkyl group. In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R ₇Is H, R₅Is H or (C)₁-C₄) Alkyl, and R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution.

In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Is substituted, and R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to fourR is₁₉And (4) substitution. In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R ₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Is substituted, and R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group.

In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R ₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl, and R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇。

In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R ₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted(C) substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl radical, R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇And R is₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R₂₂Is substituted, and R₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R₂₂And (4) substitution.

In some embodiments having the formula above, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X ₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, and R₅Is H or methyl. In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or methyl, and R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution.

In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Is substituted, and R₂Is H, (C)₁-C₆) Alkyl, (C) ₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉And (4) substitution. In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Is substituted, and R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C) ₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group.

In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl, and R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR ₁₆R₁₇。

In yet another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S，R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl radical, R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR ₁₆R₁₇And R is₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R₂₂And (4) substitution.

In some embodiments having the formula above, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, and R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S. In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, and R₇Is H. In yet another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, and R₅Is H or (C)₁-C₄) An alkyl group. In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl, and R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR ₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution.

In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Is substituted, and R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉And (4) substitution.

In yet another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R ₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Is substituted, and R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group.

In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R ₁₉Substituted, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl, and R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇。

In yet another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or (C)₁-C₄) Alkyl radical, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the phenyl OR heteroaryl group is-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R ₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl radical, R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇And R is₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R₂₂And (4) substitution.

In some embodiments having the formula above, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or methyl, and R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution. In another embodiment, X₁Is H and X₂Is H, R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R ₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are-OR₁₀Substituted and optionally substituted with one to three R₁₁Is substituted, and R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉And (4) substitution.

In yet another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R ₁₉Is substituted, and R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) An alkyl group.

In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈Is substituted and theSaid carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl, and R ₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇。

In another embodiment, X₁Is H and X₂Is H, X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or methyl, R₁Is phenyl, OR a 5-OR 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are-OR₁₀Substituted and optionally substituted with one to three R₁₁Substituted, R₂Is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, -NR₁₂R₁₃、(C₃-C₇) A carbocyclyl, or a 5-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl and heterocyclyl are optionally substituted with one to four R₁₉Substituted, R₆Is (C)₁-C₆) Hydroxyalkyl or optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, -C (O) (C)₁-C₆) Alkyl, -C (O) OH and-C (O) O (C)₁-C₆) Alkyl radical, R₈Is H, (C)₁-C₆) Haloalkyl, or (C) optionally substituted with one to three substituents each independently selected from ₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇And R is₁₀Is phenyl, or a 5-or 6-membered heteroaryl group comprising 1-3 heteroatoms selected from N, O and S, wherein the aryl and heteroaryl groups are optionally substituted with one to three R₂₂And (4) substitution.

In another embodiment, X₁And X₂Together with the carbon atom to which they are attached form ═ (O), X₃is-CH₂-，R₉Is Cl, R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S, R₇Is H, R₅Is H or methyl, R₁Is phenyl (which is substituted by-OR)₁₀Substituted and optionally substituted with one to three R₁₁Substituted), R₂Is (C)₁-C₆) Alkyl, or (C)₃-C₇) Carbocyclyl (wherein said alkyl is optionally substituted with one to four R₁₈And said carbocyclyl is optionally substituted with one to four R₁₉Substituted), R₆Is (C)₁-C₆) Hydroxyalkyl, R₈Is optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: a 4-to 7-membered heterocyclyl group containing 1-3 heteroatoms selected from N, O and S, and-C (O) NR₁₆R₁₇And R is₁₀Is substituted by one to three R₂₂A substituted phenyl group.

Example 1. a compound according to formula (I).

Embodiment 2. the compound of embodiment 1, wherein R ₄Is H or (C)₁-C₆) An alkyl group.

Embodiment 3. the compound of embodiment 1 or 2, wherein R₄Is H.

An embodiment 4. the compound of embodiment 1, wherein R₃And R₄Together with the atoms to which they are attached form a 5-membered to containing 1-3 heteroatoms selected from N, O and SA 7 membered heterocyclyl ring.

Embodiment 5. the compound of embodiment 1 or 3, wherein R₃And R₄Together with the atoms to which they are attached form a 6 membered heterocyclyl ring comprising 1-3 heteroatoms selected from N, O and S.

Embodiment 6. the compound of any of embodiments 1 to 5, wherein R₅Is H or (C)₁-C₆) An alkyl group.

Embodiment 7. the compound of any of embodiments 1 to 6, wherein R₅Is (C)₁-C₆) An alkyl group.

Embodiment 8. the compound of any of embodiments 1 to 7, wherein R₇Is H or (C)₁-C₆) An alkyl group.

An embodiment 9. the compound of any of embodiments 1-8, wherein R₇Is (C)₁-C₆) An alkyl group.

Embodiment 10. the compound of any of embodiments 1-9, wherein R₉Is a halogen.

Embodiment 11. the compound of any of embodiments 1-10, wherein R₉Is chlorine.

Embodiment 12. the compound of any of embodiments 1-11, wherein R ₈Is optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C)₃-C₇) Carbocyclyl, 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, -NR₁₆R₁₇and-C (O) NR₁₆R₁₇。

Embodiment 13. the compound of any of embodiments 1 to 12, wherein R₈Is (C)₁-C₆) An alkyl group.

Embodiment 14. the compound of embodiment 1 having formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), or formula (Ii).

Embodiment 15. the compound of any of embodiments 1 to 14, wherein R₁Is phenyl, which is-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution.

Embodiment 16. the compound of any of embodiments 1 to 14, wherein R₁Is a pyridyl radical, which is-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution.

An embodiment 17. the compound of embodiment 1 having formula (Ij), formula (Ik), formula (Im), or formula (Io) wherein x is 0, 1, or 2.

Embodiment 18. the compound of any of embodiments 1 to 17, wherein R₁₀Is phenyl, which is substituted by one to three R₂₂And (4) substitution.

Embodiment 19. the compound of any of embodiments 1-17, wherein R₁₀Is a pyridyl group, which is substituted by one to three R ₂₂And (4) substitution.

Example 20. the compound (Cmd) according to example 1, selected from

An embodiment 21. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

A combination comprising a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutically active agents.

Embodiment 23. the combination of embodiment 22, wherein the additional therapeutically active agent is a statin.

Embodiment 24 the pharmaceutical composition according to embodiment 21 or the combination according to embodiment 22 or 23 for use in treating, preventing, ameliorating or delaying the progression of a PCSK 9-mediated disease or disorder.

Embodiment 25 the pharmaceutical composition or combination of embodiment 24, wherein the PCSK 9-mediated disease or disorder or the disease or disorder in which inhibition of PCSK9 activity is desired is selected from the group consisting of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis and xanthoma.

Embodiment 26 a method of modulating PCSK9 comprising administering to a patient in need thereof a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof.

Embodiment 27 a method of inhibiting PCSK9 comprising administering to a patient in need thereof a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof.

Embodiment 28 a method of treating, preventing, ameliorating or delaying the progression of a PCSK 9-mediated disease or disorder, the method comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof.

Embodiment 29 the method of embodiment 28, wherein the PCSK 9-mediated disease or disorder is selected from the group consisting of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis and xanthoma.

Example 30 a method of (i) lowering lp, (a), (ii) lowering lp (a) plasma levels, (iii) lowering lp (a) serum levels, (iv) lowering serum TRL or LDL levels, (v) lowering serum triglyceride levels, (vi) lowering LDL-C, (vii) lowering total plasma apoB concentration, (viii) lowering LDL apoB, (ix) lowering TRL apoB, or (x) lowering non-HDL-C levels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of examples 1-20, or a pharmaceutically acceptable salt thereof, thereby lowering LDL-C in the patient.

Embodiment 31 the method of any one of embodiments 26-30, wherein administering is performed orally, parenterally, subcutaneously, by injection, or by infusion.

Embodiment 32 a compound according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of a PCSK 9-mediated disease or disorder.

Embodiment 33. the compound according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, amelioration or delay of progression, or for use in the treatment, prevention, amelioration or delay of progression of a disease or disorder for which inhibition of PCSK9 is indicated.

Embodiment 34 the use of a compound according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, for the treatment, prevention, amelioration or delay of progression of a PCSK 9-mediated disease or disorder or for the treatment, prevention, amelioration or delay of progression of a disease or disorder in which inhibition of PCSK9 is indicated.

Embodiment 35 use of a compound according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, ameliorating or delaying the progression of a PCSK 9-mediated disease or disorder or for treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK 9.

Embodiment 36 a method for treating, preventing, ameliorating or delaying the progression of a PCSK 9-mediated disease or disorder or a disease or disorder for which inhibition of PCSK9 or PCSK9 activity is desired, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof.

Example 37 a compound for use according to example 33, a use according to example 34 or 35 or a method according to example 36, wherein the PCSK 9-mediated disease or disorder or the disease or disorder in which inhibition of PCSK9 is desired is selected from the group consisting of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis and xanthoma.

Embodiment 38. the compound according to embodiment 1, selected from:

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone; and

(3S,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

An embodiment 39. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1-20 and embodiment 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Embodiment 40 the pharmaceutical composition of embodiment 39, further comprising at least one additional agent.

Embodiment 41 the pharmaceutical composition according to embodiment 39 or embodiment 40 for use in the treatment of a PCSK9 mediated disease or disorder.

Embodiment 42. a method of modulating PCSK9 comprising administering to a patient in need thereof a compound according to any one of embodiments 1-20 and embodiment 38, or a pharmaceutically acceptable salt thereof.

Embodiment 43. a method of inhibiting PCSK9 comprising administering to a patient in need thereof a compound according to any one of embodiments 1-20 and embodiment 38, or a pharmaceutically acceptable salt thereof.

Embodiment 44. a method of inhibiting PCSK9 activity comprising administering to a patient in need thereof a compound according to any one of embodiments 1-20 and embodiment 38, or a pharmaceutically acceptable salt thereof.

Embodiment 45 a method of treating a PCSK 9-mediated disease or disorder, the method comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of examples 1-20 and example 38, or a pharmaceutically acceptable salt thereof.

Embodiment 46. the method of embodiment 45, wherein the PCSK 9-mediated disease or disorder is selected from the group consisting of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

Embodiment 47. a method of reducing LDL-C in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of embodiments 1-20 and 38, or a pharmaceutically acceptable salt thereof, thereby reducing LDL-C in the patient.

Embodiment 48 the method of any one of embodiments 42 to 47, wherein administration is oral, parenteral, subcutaneous, by injection, or by infusion.

Embodiment 49. a compound according to any one of embodiments 1 to 20 and embodiment 38, or a pharmaceutically acceptable salt thereof, for use in the treatment of a PCSK 9-mediated disease or disorder.

Example 50 a compound according to any one of examples 1-20 and example 38, or a pharmaceutically acceptable salt thereof, for use in the treatment of a PCSK9 mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

Embodiment 51 use of a compound according to any one of embodiments 1 to 20 and embodiment 38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a PCSK 9-mediated disease or disorder.

The use of claim 51, wherein said PCSK9 mediated disease or disorder is selected from the group consisting of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

An embodiment 53-a compound according to any one of embodiments 1 to 20 and embodiment 38, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease associated with the inhibition of PCSK9 activity.

Embodiment 54 the use of a compound according to any one of embodiments 1 to 20 and embodiment 38, or a pharmaceutically acceptable salt thereof, in the treatment of a disease associated with the inhibition of PCSK9 activity.

Embodiment 55 the use according to embodiment 54, wherein the disease associated with inhibition of PCSK9 activity is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

Example 56A method of making a compound having the formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,

(d) alkylating a compound having formula (IIa) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,

wherein R is₅Is H and R₉As defined above for formula (I),

the alkylation is carried out using an alkyl halide and a base in a solvent and at low temperature to provide a compound having formula (IIb),

(e) Reacting a compound having formula (IIb) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof with an acid in a solvent, followed by Boc₂Reacting O with a base to form a compound having formula (IIc),

wherein R is₅Is (C)₁-C₆Alkyl) and R₉Is as defined above for formula (I), a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof;

(f) alkylating a compound having formula (IIc), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof, using an alkylating agent in a solvent and optionally a metal oxide, to provide a compound having formula (IId),

wherein R is_a1And R₅Each independently is (C)₁-C₆Alkyl) and R₉Is as defined above for formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof; and

(d) dealkylation of the compound of formula (IId) with a palladium catalyst and N, N-dimethyltrimethylsilylamine in a solvent provides the compound of formula (II).

Embodiment 57. the method of embodiment 56, wherein the solvent in step (a) is DMF.

Embodiment 58. the method of embodiment 56 or 57, wherein the temperature in step (a) is about 0 ℃.

Embodiment 59. the method of any one of embodiments 56 to 58, wherein the acid in step (b) is trifluoroacetic acid (TFA).

Embodiment 60. the method of any of embodiment 56-59, wherein a metal oxide is used in step (c).

Embodiment 61. the method of embodiment 60, wherein the metal oxide is silver (I) oxide (Ag)₂O)。

Embodiment 62. the method of any one of embodiments 56-61, wherein the palladium catalyst in step (d) is tetrakis (triphenylphosphine) palladium (0).

Embodiment 63A method of making a compound having formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,

wherein R is_a1Is H, R₅Is (C)₁-C₆Alkyl) and R₉Is as defined above for formula (I), the method comprising reacting a compound having formula (IIb):

wherein R is₅Is (C)₁-C₆Alkyl) and R₉Is as defined above for formula (I), with a palladium catalyst and N, N-dimethyltrimethylsilylamine in a solvent to provide a compound having formula (II).

Embodiment 64. the method of embodiment 63, wherein the solvent is in dichloromethane.

Embodiment 65. the method of embodiment 63 or 64, wherein the palladium catalyst is tetrakis (triphenylphosphine) palladium (0).

In another embodiment, the compound having formula (I) is selected from:

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone; and

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone.

Another aspect of the disclosure relates to an intermediate having formula (IIIa):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R is_cis-NH₂、-NH(C₁-C₆) Alkyl, -C (O) NH₂Or

Wherein R represents a chiral center_dIs H or a nitrogen protecting group (e.g., tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.) and R₉Is as defined above for formula (I). In one embodiment, R _dIs a nitrogen protecting group. In another embodiment, R_dIs tert-butyloxycarbonyl (Boc). In another embodiment, R_dIs H.

Another aspect of the disclosure relates to an intermediate having formula (IIIb):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R is_dIs H or a nitrogen protecting group (e.g., tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.), R_eIs H or-C (O) OCH₂CH＝CH₂，R₇Is H and R₅、R₆And R₉Is as defined above for formula (I). In one embodiment, R_dIs a nitrogen protecting group. In another embodiment, R_dIs tert-butyloxycarbonyl (Boc). In another embodiment, R_dIs H.

Another aspect of the disclosure relates to an intermediate having formula (IIIc):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R is_dAnd R_fEach independently is H or a nitrogen protecting group (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.), and R is₁、R₅、R₆、R₇、R₈And R₉Is as defined above for formula (I). In one embodiment, R_dIs a nitrogen protecting group. In another embodiment, R_dIs tert-butyloxycarbonyl (Boc). In another embodiment, R _dIs H. In one embodiment, R_fIs a nitrogen protecting group. In another embodiment, R_fIs tert-butyloxycarbonyl (Boc). In another embodiment, R_fIs H.

Another aspect of the disclosure relates to an intermediate having formula (IIId):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R is_fIs H or a nitrogen protecting group (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.), R_gis-OH or-O (C)₁-C₆) Alkyl radical, X₁And X₂Together with the carbon atom to which they are attachedForm (O), X₃is-CH₂-, and R₁、R₂、R₅、R₆、R₇、R₈And R₉Is as defined above for formula (I). In one embodiment, R_fIs a nitrogen protecting group. In another embodiment, R_fIs tert-butyloxycarbonyl (Boc). In another embodiment, R_fIs H.

Another aspect of the disclosure relates to an intermediate having formula (IIIe) or (IIIf):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof, wherein R is_His-OH, -O (C)₁-C₆) Alkyl, -O triflate, or halogen, and R₁₀And R₁₁Is as defined above for formula (I).

Another aspect of the disclosure relates to an intermediate having formula (IIIg) or (IIIh):

Another aspect of the disclosure relates to an intermediate having formula (IIIi) or (IIIj):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or inter-thereofA variant wherein R_His-OH, -O (C)₁-C₆) Alkyl, -O triflate, or halogen, and R₂₂Is as defined above for formula (I).

Another aspect of the disclosure relates to an intermediate selected from the group consisting of:

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof.

In another embodiment of the disclosure, the compound having formula (I) is an enantiomer. In some embodiments, the compound is the (S) -enantiomer. In other embodiments, the compound is the (R) -enantiomer. In other embodiments, the compound of formula (I) may be the (+) or (-) enantiomer.

In another embodiment of the disclosure, intermediates (IIIa), (IIIb), (IIIc), and (IIId) are enantiomers. In some embodiments, the intermediate is the (S) -enantiomer. In other embodiments, the intermediate is the (R) -enantiomer. In other embodiments, the intermediate may be the (+) or (-) enantiomer.

In another embodiment of the disclosure, the compound having formula (I) is a diastereomer. In another embodiment of the disclosure, the intermediates having formula (IIIa), (IIIb), (IIIc), and (IIId) are diastereomers.

It is understood that all isomeric forms are included in the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis-or trans-configuration. All tautomeric forms are also intended to be included.

The compounds and intermediates of the present disclosure and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs thereof can exist in their tautomeric form (e.g., as an amide or imino ether). All such tautomeric forms are considered herein as part of the present disclosure.

The compounds and intermediates of the present disclosure may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds and intermediates of the present disclosure and mixtures thereof (including racemic mixtures) form part of the present disclosure. In addition, the present disclosure includes all geometric and positional isomers. For example, if a compound or intermediate of the disclosure contains a double bond or fused rings, both cis and trans forms, as well as mixtures, are included within the scope of the disclosure. Each compound or intermediate disclosed herein includes all enantiomers that conform to the general structure of the compound or intermediate. The compounds or intermediates may be in racemic or enantiomerically pure form, or in any other form with respect to stereochemistry. The assay results may reflect data collected for racemic forms, enantiomerically pure forms, or any other form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated as follows: the enantiomeric mixtures are converted into diastereomeric mixtures by reaction with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or a morser's acid chloride), the diastereomers are separated, and the individual diastereomers are converted (e.g., hydrolyzed) to the corresponding pure enantiomers. In addition, some compounds of the present disclosure may be atropisomers (e.g., substituted biaryls) and are considered part of the present disclosure. Enantiomers can also be separated using a chiral HPLC column.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. Further, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.

All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the present disclosure (including salts, solvates, esters, and prodrugs of those compounds, and salts, solvates, and esters of prodrugs), such as those that may exist due to asymmetric carbons on different substituents (including enantiomeric forms (where asymmetric carbons may even be present), rotameric forms, atropisomers, and diastereomeric forms), are included within the scope of the present disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (for example, if the compound having formula (I) contains a double bond or fused ring, both the cis and trans forms and mixtures are included within the scope of this disclosure. Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or may, for example, be as racemates or mixed with all other, or other selected, stereoisomers. Chiral centers of the present disclosure may have the S configuration or the R configuration as defined by the IUPAC1974 recommendation. The use of the terms "salt," "solvate," "ester," "prodrug," and the like, is intended to apply equally to the salts, solvates, esters, and prodrugs of the enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the inventive compounds.

The compounds of formula (I) may form salts, which are also within the scope of the present disclosure. Unless otherwise indicated, reference to a compound having a formula herein is understood to include reference to a salt thereof.

The present disclosure relates to compounds that are modulators of PCSK 9. In one embodiment, a compound of the disclosure is a PCSK9 inhibitor.

The present disclosure relates to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, as well as pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

Activity of the Compound

The activity of compounds according to the present disclosure as PCSK9 inhibitors may be assessed using a time resolved fluorescence resonance energy transfer (TR-FRET) assay. The time-resolved fluorescence resonance energy transfer (TR-FRET) assay measures the ability of compounds of the present disclosure to interfere with the binding of human PCSK9 to human LDLR, providing measurements of potency (IC50) and efficacy (Amax).

Solutions of varying concentrations were prepared by diluting compounds of the disclosure in dimethyl sulfoxide (DMSO), and the resulting solutions were pipetted onto plates. DMSO was used as a negative control. Intermediate plates were prepared by transferring known amounts of each compound solution and control from the compound plate to the corresponding wells containing assay buffer and mixing well. The third plate was then prepared for assay by adding human PCSK9 Alexa Fluor 647, followed by the addition of known amounts of each solution from the intermediate plate. Unlabeled human PCSK9 in assay buffer containing DMSO was used as a positive control for the assay. After incubation, the human LDLR extracellular domain-Europium krypton (Europium Kryptate) was added to each well of the assay plate and the resulting mixture was incubated for an additional period of time. TR-FRET signals were measured and the IC of the compounds was calculated using the FRET ratio (FRET/europium) ₅₀And Amax.

Synthesis method of compound

The compounds of the present disclosure can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routes are described in the schemes given below.

The compounds of formula (I) may be prepared by methods known in the art of organic synthesis, as illustrated in part by the synthetic schemes below. In the schemes described below, it is well understood that protective groups for sensitive or reactive groups are used as necessary according to general principles or chemistry. The protecting Groups were manipulated according to standard methods of Organic Synthesis (T.W.Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis [ protecting Groups in Organic Synthesis ]", third edition, Wiley [ Wei Li Press ], New York 1999). These groups are removed at a convenient stage of compound synthesis using methods apparent to those skilled in the art. The selection process as well as the reaction conditions and their order of execution should be consistent with the preparation of the compound having formula (I).

One skilled in the art will recognize whether a stereocenter is present in the compound having formula (I). Thus, the present disclosure includes both possible stereoisomers (unless indicated in the synthesis) and includes not only racemic compounds, but also individual enantiomers and/or diastereomers. When the compounds are desired as single enantiomers or diastereomers, they may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. The resolution of the final product, intermediate or starting material may be effected by any suitable method known in the art. See, e.g., "stereospecificity of Organic Compounds ]" authors E.L.Eliel, S.H.Wilen, and L.N.Mander (Wiley-lnterscience, 1994).

The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic methods.

Preparation of the Compounds

The compounds of the present disclosure can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present disclosure can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The compounds of the present disclosure can be synthesized by following the steps outlined in general schemes 1 and 2, which include the order of the different assembly intermediates 1-a, 1-b, 1-c, 1-d, 1-e, 1-f, 1-g, 1-h, 1-i, 2-a, 2-b, 2-c, 2-d, and 2-e. Starting materials are commercially available or prepared by known procedures in the literature or as indicated.

General scheme 1

Wherein R is₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈And R₉Is defined in formula (I), X₃Is CH₂，X₁And X₂Together with the carbon atom to which they are attached, form ═ (O), and P is an amine protecting group (e.g., tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.).

General procedures for preparing compounds having formula (I) by using intermediates 1-a, 1-b, 1-c, 1-d, 1-e, 1-f, 1-g, 1-h and 1-I are outlined in general scheme 1. Treatment of 1-a with PS-2-chlorotrityl chloride resin in the presence of a base (e.g., Triethylamine (TEA), N-Diisopropylethylamine (DIPEA), etc.) and in a solvent (e.g., Dichloromethane (DCM), Dimethylformamide (DMF), etc.) affords 1-b. The synthesis of intermediates 1-d can be accomplished by: amide coupling agents (e.g., 2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium-tetrafluoroborate (TBTU), O- (1H-6-chlorobenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium Hexafluorophosphate (HCTU), or O- (7-azobenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium Hexafluorophosphate (HATU), etc.) and optionally a base (e.g., TEA, DIPEA, etc.) are used in a solvent (e.g., N-methylpyrrolidine (NMP) or DMF) in a resin (e.g., TentaGel ^TMScram resin) with 1-c followed by removal of the amine protecting group P (e.g. 4-methylpiperidine/DMA treatment to remove the Fmoc group). Coupling of 1-d with an acid 1-e using an amide coupling reagent (e.g., TBTU, HCTU, HATU, etc.) and optionally a base (e.g., TEA, DIPEA, etc.), followed by deprotection (e.g., removal of the Fmoc group with 4-methylpiperidine/DMA treatment or removal of the Boc group with TFA treatment) affords 1-f.

Cleavage of 1-f from the resin by repeated treatment with 1,1,1,3,3, 3-hexafluoropropan-2-ol (HFIP) in a solvent such as DCM provides 1-g. Reductive amination of amines 1-g and aldehydes 1-h in a reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc.), optionally in the presence of an acid (e.g., acetic acid (AcOH)), in a solvent (e.g., methanol (MeOH) and/or DCM) affords 1-i. Cyclization of 1-I in a solvent (e.g., DCM, NMP, DMF, etc.) using standard coupling conditions (e.g., amide coupling agents (e.g., HATU, HOAt, TBTU, and/or HCTU)), an optional base (e.g., 2, 6-lutidine, TEA, DIPEA, etc.) provides the desired compound of formula (I).

General scheme 2

Wherein R is₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈And R₉Is defined in formula (I), X₃Is CH₂，X₁And X₂Together with the carbon atom to which they are attached form ═ (O), R' is an alkyl group, and P is an amine protecting group (e.g., tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.).

Alternatively, compounds having formula (I) may be prepared by using intermediates 1-c, 1-e, 1-h, 1-I, 2-a, 2-b, 2-c, 2-d and 2-e as outlined in general scheme 2. The synthesis of intermediate 2-c can be accomplished by: coupling 2-a to 2-b in a solvent (e.g., NMP, DMF, etc.) using an amide coupling agent (e.g., TBTU, HCTU, HATU, etc.) and optionally a base (e.g., TEA, DIPEA, etc.) under standard coupling conditions, followed by removal of the amine protecting group P (e.g., 4-methylpiperidine/DMA treatment to remove the Fmoc group). Coupling of amine 2-c and acid 1-c using an amide coupling reagent (e.g., TBTU, HCTU, HATU, etc.) and optionally a base (e.g., TEA, DIPEA, etc.), followed by deprotection (e.g., removal of the Fmoc group with 4-methylpiperidine/DMA treatment or removal of the Boc group with TFA treatment) provides 2-d. The coupling and deprotection steps were repeated in step 3 using standard coupling conditions as described above to provide intermediate 2-e. Reductive amination of amines 2-e and aldehydes 1-h in a solvent (e.g., MeOH and/or DCM) in the presence of a reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride), and optionally an acid (e.g., AcOH), followed by hydrolysis of the ester with an acid (e.g., TFA) in a solvent (e.g., DCM) provides 1-i. Cyclization of 1-I in a solvent (e.g., DCM, NMP or DMF) using standard coupling conditions (e.g., amide coupling agents (e.g., HATU, HOAt, TBTU and/or HCTU)), an optional base (e.g., 2, 6-lutidine, TEA or DIPEA) provides the desired compound of formula (I).

It is to be understood that in the description and formulae shown above, each radical X₁、X₂、X₃、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈And R₉And other variables are as defined above unless otherwise indicated. Furthermore, for synthetic purposes, the compounds of general schemes 1 and 2 are merely representative of groups having choice to illustrate the general synthetic methods of compounds having formula (I) as defined herein.

Methods of use of the disclosed compounds

Another aspect of the present disclosure is directed to a method of modulating PCSK 9. The method comprises administering to a patient in need thereof an effective amount of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

In another aspect, the disclosure is directed to methods of inhibiting PCSK 9. The method involves administering to a patient in need thereof an effective amount of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

Another aspect of the disclosure relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in which PCSK9 plays a role. The methods comprise administering to a patient in need of treatment for a disease or disorder in which PCSK9 plays a role an effective amount of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with the inhibition of PCSK9 in a patient, comprising administering to a patient in need thereof an effective amount of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

In another aspect, the disclosure relates to methods of treating, preventing, inhibiting, or eliminating PCSK 9-mediated diseases or disorders. The methods comprise administering to a patient in need of treatment for a PCSK 9-mediated disease or disorder an effective amount of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

Another aspect of the disclosure relates to a method of treating, preventing, inhibiting or eliminating: hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, sepsis, elevated lp (a), elevated LDL, elevated TRL, or elevated triglycerides. The method comprises administering to a patient in need of treatment an effective amount of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

In another aspect, the disclosure relates to a method of reducing lp (a), reducing lp (a) plasma levels, reducing lp (a) serum levels, reducing serum TRL or LDL levels, reducing serum triglyceride levels, reducing LDL-C, reducing total plasma apoB concentrations, reducing LDL apoB, reducing TRL apoB or reducing non-HDL-C. The method comprises administering to a patient in need thereof an effective amount of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

In another aspect, the disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of diseases or disorders in which PCSK9 plays a role.

Another aspect of the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of a disease associated with the inhibition of PCSK 9.

Another aspect of the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, sepsis, lp (a) elevation, LDL elevation, TRL elevation, or triglyceride elevation.

In another aspect, the disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in lowering lp (a), lowering lp (a) plasma levels, lowering lp (a) serum levels, lowering serum TRL or LDL levels, lowering serum triglyceride levels, lowering LDL apoB, lowering TRL apoB, or lowering non-HDL-C.

Another aspect of the present disclosure relates to the use of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for the treatment, prevention, inhibition, or elimination of diseases or disorders in which PCSK9 plays a role.

In another aspect, the disclosure relates to the use of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for inhibiting PCSK 9.

In another aspect, the present disclosure relates to the use of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, sepsis, lp (a) elevation, LDL elevation, TRL elevation, or triglyceride elevation.

Another aspect of the disclosure relates to the use of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for reducing lp (a), reducing lp (a) plasma levels, reducing lp (a) serum levels, reducing serum TRL or LDL levels, reducing serum triglyceride levels, reducing LDL apoB, reducing TRL apoB, or reducing non-HDL-C.

In another aspect, the disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for the treatment of a disease associated with the inhibition of PCSK 9.

Another aspect of the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for the treatment of a disease in which PCSK9 plays a role.

In another aspect, the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthoma, peripheral arterial disease, sepsis, lp (a) elevation, LDL elevation, TRL elevation, or triglyceride elevation.

Another aspect of the disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for reducing lp (a), lowering lp (a) plasma levels, lowering lp (a) serum levels, lowering serum TRL or LDL levels, lowering serum triglyceride levels, lowering LDL apoB, lowering TRL apoB, or lowering non-HDL-C.

In another aspect, the disclosure relates to the use of an inhibitor of PCSK9 in the manufacture of a medicament for the treatment, prevention, inhibition, or elimination of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis, or xanthoma.

Another aspect of the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in treating a PCSK 9-mediated disease or disorder.

Another aspect of the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in treating a PCSK 9-mediated disease or disorder selected from the group consisting of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis, and xanthoma.

In another aspect, the present disclosure relates to the use of a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment of a PCSK 9-mediated disease or disorder.

Another aspect of the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for the treatment of a PCSK 9-mediated disease or disorder.

In another aspect, the present disclosure relates to a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use as a medicament.

The disclosure also relates to the use of an inhibitor of PCSK9 in the manufacture of a medicament for the treatment, prevention, inhibition, or elimination of a disease or condition in which PCSK9 plays a role, wherein the medicament comprises a compound having formula (I).

In another aspect, the disclosure relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a PCSK 9-mediated disease or condition, wherein the medicament comprises a compound or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer of formula (I) or a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer of formula (I), and a pharmaceutically acceptable carrier.

In some embodiments of the above methods, the PCSK 9-mediated disease or disorder, the disease or disorder in which PCSK9 plays a role, the disease or disorder in the patient associated with inhibition of PCSK9, and the disease associated with inhibition of PCSK9 is selected from the group consisting of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis and xanthoma.

The compounds of the present disclosure are useful for reducing or decreasing low density lipoprotein cholesterol (LDL-C) in a subject in need thereof. The subject may have a continuously elevated LDL-C level. In some embodiments, the subject's plasma level of LDL-C is consistently above 70mg/dL, e.g., above 80mg/dL, 90mg/dL, 100mg/dL, 110mg/dL, 120mg/dL, 130mg/dL, 140mg/dL, 150mg/dL, 160mg/dL, 170mg/dL, 180mg/dL, or 190mg/dL, or higher. The compounds of the present disclosure may also be used to reduce or reduce non-high density lipoprotein cholesterol (non-HDL-C) or total cholesterol in an individual in need thereof.

The disclosure also relates to methods for improving blood cholesterol markers associated with increased risk of heart disease. These markers include high total cholesterol, high LDL, high total cholesterol to HDL ratio, and high LDL to HDL ratio. Total cholesterol below 200mg/dL is considered desirable, cholesterol from 200mg/dL to 239mg/dL is considered critically high, and cholesterol at 240mg/dL and above is considered high.

In another aspect, the present disclosure provides a method of reducing LDL-C, non-HDL-C and/or total cholesterol in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound or a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier described herein.

In another embodiment, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, of the disclosure and a pharmaceutically acceptable carrier, for use in the treatment of a disease, including, but not limited to, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis, and xanthoma.

In one embodiment, a method is provided for treating a disease or disorder in which PCSK9 plays a role, the diseases or disorders include hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, lp (a) elevation, LDL elevation, TRL elevation, triglyceride elevation, sepsis and xanthoma, the method comprises administering to a patient suffering from at least one of the diseases or disorders a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

The disclosed compounds of the present disclosure can be administered in an effective amount to treat or prevent a disorder and/or prevent its development in a subject.

Administration, pharmaceutical compositions and dosages of the disclosed compounds

Administration of the disclosed compounds can be accomplished via any mode of administration of the therapeutic agent. These include systemic or topical administration, for example oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration.

Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, and the like, sometimes in unit doses, and consistent with conventional pharmaceutical practice. They can also be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, and all uses are well known to those skilled in the pharmaceutical arts.

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound having formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, diluent, or surfactant. In further embodiments, the compositions comprise at least two pharmaceutically acceptable carriers (such as those described herein). The pharmaceutical compositions can be formulated for a particular route of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical compositions of the present disclosure may be made in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories), or in liquid form (including but not limited to solutions, suspensions, or emulsions). Tablets may be coated with a film or enteric coating according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising the active ingredient and one or more of the following:

a) Diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine;

b) lubricants, for example, silica, talc, stearic acid, magnesium or calcium salts thereof and/or polyethylene glycol; in the case of tablets, further comprising

c) Binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone; if desired

d) Disintegrating agents, for example, starch, agar, alginic acid or its sodium salt or effervescent mixtures; and

e) adsorbents, coloring agents, flavoring agents, and sweetening agents.

Liquid (especially injectable) compositions may be prepared, for example, by dissolution, dispersion, and the like. For example, the disclosed compounds are dissolved in or mixed with a pharmaceutically acceptable solvent (such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like), thereby forming an injectable isotonic solution or suspension. Proteins (e.g., albumin, chylomicron, or serum proteins) can be used to solubilize the disclosed compounds.

The disclosed compounds may also be formulated as suppositories, which may be prepared as fatty emulsions or suspensions; a polyalkylene glycol (e.g., propylene glycol) is used as the carrier.

Parenteral injectable administration is commonly used for subcutaneous, intramuscular or intravenous injection and infusion. Injectables can be prepared in conventional forms (either as liquid solutions or suspensions, or solid forms suitable for dissolution in liquid prior to injection).

The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions of the invention can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20%, by weight or volume of the disclosed compounds, of the disclosed compounds.

The dosage regimen utilizing the disclosed compounds is selected in accordance with a variety of factors including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; renal or hepatic function of the patient; and the particular compounds disclosed for use. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

When used for the indicated effects, an effective dosage of the disclosed compounds, the disclosed pharmaceutical compositions, or the disclosed combinations ranges from about 0.5mg to about 5000mg of the disclosed compounds required to treat the disorder. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000mg of the disclosed compounds, or a range of amounts from one to another in a dosage list. In one embodiment, the composition is in the form of a tablet that can be scored. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age of the subject and the individual condition, disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient which is necessary to prevent, treat or inhibit the condition or disease progression.

The above dose profiles are demonstrated in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and preparations thereof. The compounds of the present disclosure can be administered in vitro in the form of solutions (e.g., aqueous solutions), and enterally, parenterally, advantageously intravenously, e.g., as suspensions or in vivo in aqueous solutions. The in vitro dose may be between about 10-3 molar and 10-9 molar. Depending on the route of administration, the therapeutically effective amount in vivo may range between about 0.1-500mg/kg, or between about 1-100 mg/kg.

Combination therapy

The compounds of the present disclosure may be administered in a therapeutically effective amount in combination therapy with one or more therapeutic agents (drug combination) or means (e.g., non-drug therapy). For example, synergy may occur with other cardiovascular agents, antihypertensive agents, coronary vasodilators, and diuretics. When the compounds of the present application are administered in combination with other therapies, the dosage of the co-administered compounds will, of course, vary depending upon the type of combination employed, the particular drug employed, the condition being treated, and the like.

The compounds of the present disclosure may be administered concurrently with one or more other therapeutic agents or before or after the therapeutic agent. The compounds of the present disclosure may be administered separately, by the same or different routes of administration, or together in the same pharmaceutical composition as the other agent. A therapeutic agent is, for example, a chemical compound, peptide, antibody fragment, or nucleic acid that has therapeutic activity or enhances therapeutic activity when administered to a patient in combination with a compound of the disclosure.

In one embodiment, the disclosure provides a product comprising a compound of the disclosure and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or disorder mediated by PCSK 9. Products provided as a combined preparation include compositions comprising a compound of the disclosure and one or more other therapeutic agents together in the same pharmaceutical composition, or a compound of the disclosure and one or more other therapeutic agents in separate forms (e.g., in the form of a kit).

In another aspect, the disclosure includes compounds having formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), formula (Ij), formula (Ik), formula (Im), formula (Io), compounds described according to any one of example numbers 1 to 20 or example 38, or any embodiment of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), formula (Ij), formula (Ik), formula (Im) and/or formula (Io) described herein, or a pharmaceutically acceptable salt thereof, for use in combination therapy. A compound, composition, medicament and compound having formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), formula (Ij), formula (Ik), formula (Im), formula (Io), a compound according to any one of example numbers 1 to 20 or example 38, or any of the examples of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), formula (Ij), formula (Ik), formula (Im) and/or formula (Io) described herein, or a pharmaceutically acceptable salt thereof, for use may advantageously be used in combination with one or more other therapeutic agents.

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, a pharmaceutically acceptable carrier, and one or more therapeutic agents. The pharmaceutically acceptable carrier may further include an excipient, diluent, or surfactant.

Combination therapy includes further administration of the compound to a subject in combination with other bioactive ingredients (such as, but not limited to, a second agent, such as, but not limited to, a cardiovascular agent, an adrenergic blocker, an antihypertensive agent, an angiotensin system inhibitor, an Angiotensin Converting Enzyme (ACE) inhibitor, a coronary vasodilator, a diuretic or adrenergic stimulant or a second agent targeting PCSK 9) and non-drug therapy (such as, but not limited to, surgery or radiation therapy). For example, the compounds of the present application may be used in combination with other pharmaceutically active compounds, preferably compounds capable of enhancing the effect of the compounds of the present application. The compounds of the present application may be administered to other drug therapies or treatment modalities simultaneously (as single or separate formulations) or sequentially. In general, combination therapy contemplates administration of two or more drugs during a single cycle or course of treatment.

In some embodiments, the compounds of the present application may be used in combination with agents known to be beneficial for lowering cholesterol (including LDL-C, non-HDL-C, triglyceride-lowering agents, and total cholesterol) and/or raising HDL-C.

Exemplary therapeutic agents that may be used in combination with the compounds of the present disclosure include, but are not limited to, hypolipidemic agents, niacin and analogs thereof, bile acid sequestrants, thyroid hormone mimetics, Thyroid Hormone Receptor (THR) β -selective agonists, microsomal triglyceride transfer protein (MTP) inhibitors, acyl CoA: diacylglycerol acyltransferase 1(DGAT1) inhibitors, Niemann Pick (Niemann Pick) C1-like 1(NPC1-L1) inhibitors, agonists of ATP-binding cassette (ABC) protein G5 or G8, inhibitory nucleic acids targeting PCSK9, inhibitory nucleic acids targeting apoB100, apoA-I up-regulator/inducer, ABCA1 stabilizers or inducers, phospholipid transfer protein (PLTP) inhibitors, fish oils, anti-diabetic agents, anti-obesity agents, peroxisome proliferator activator receptor agonists, ATP Citrate Lyase (ACL) inhibitors, and anti-hypertensive agents.

Examples of hypolipidemic agents that may be used in combination with the compounds of the present disclosure include, but are not limited to, HMG-CoA reductase inhibitors, squalene synthase inhibitors, LXR agonists, FXR agonists, fibrates, cholesterol absorption inhibitors, nicotinic acid bile acid binding resins, niacin and other GPR109 agonists, and aspirin.

HMG-CoA reductase inhibitors (i.e., statins) are a class of drugs used to lower cholesterol levels by inhibiting HMG-CoA reductase, which plays an important role in the production of cholesterol in the liver. Elevated cholesterol levels are associated with cardiovascular diseases and statins are therefore useful in the prevention of these diseases. Exemplary statins include, but are not limited to, atorvastatin, cerivastatin, mevastatin, pravastatin, dihydromevastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and a vistatin thereof, or a pharmaceutically acceptable salt thereof.

Fibrates or fibric acid derivatives lower triglycerides and raise HDL cholesterol. They may have little effect on LDL cholesterol. For example, gemfibrozil or fenofibrate can be used in humans with very high triglyceride levels or low HDL levels and high triglyceride levels. Gemfibrozil may be used to reduce the risk of heart attack in coronary heart disease (CAD) patients with low HDL and high triglycerides. Examples of fibrates include, but are not limited to, clofibrate, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate.

Cholesterol absorption inhibitors are a class of compounds that prevent the absorption of cholesterol from the small intestine into the circulatory system and, in turn, lower the plasma LDL-C concentration. Elevated cholesterol levels are associated with increased CVD risk; therefore, cholesterol absorption inhibitors are used with the aim of reducing the risk of CVD. A non-limiting example of a cholesterol absorption inhibitor is ezetimibe, previously known as "Sch-58235". Another example is Sch-48461. Both compounds were developed by the company of Xianlingpaya (Schering-Plough).

Examples of bile acid sequestrants that may be used in combination with the compounds of the present disclosure include, but are not limited to, cholestyramine, colesevelam, and colesevelam.

A non-limiting example of a thyroxine mimetic that may be used in combination with a compound of the present disclosure is compound KB 2115.

A non-limiting example of a Thyroid Hormone Receptor (THR) β -selective agonist that may be used in combination with the compounds of the present disclosure is MGL-3196.

DGAT is an enzyme that catalyzes the last step in triacylglycerol biosynthesis. DGAT catalyzes the coupling of 1, 2-diacylglycerol to fatty acyl-CoA, producing coenzyme a and triacylglycerol. Two enzymes have been identified that exhibit DGAT activity: DGAT1 (acyl coA-diacylglycerol acyltransferase 1, see Cases et al, Proc. Natl. Acad. Sci [ Proc. Sci. USA ] 95: 13018-. There was no significant protein sequence homology between DGAT1 and DGAT 2. Importantly, DGAT1 knockout mice were protected from high fat diet-induced weight gain and insulin resistance (Smith et al, Nature Genetics [ Nature Genetics ]25:87-90,2000). The phenotype of DGAT1 knockout mice indicates that DGAT1 inhibitors may be useful in the treatment of obesity and obesity-related complications. DGAT1 inhibitors useful in the combination are compounds and analogues disclosed generally and specifically in the following, such as WO 2007/126957 and WO 2009/040410, in particular in the compound claims, as well as the end products of the working examples, the subject matter of the end products, pharmaceutical preparations and the claims.

Examples of DGAT1 inhibitors suitable for use in combination with the compounds of the present disclosure include, but are not limited to {4- [4- (3-methoxy-5-phenylamino-pyridin-2-yl) -phenyl ] -cyclohexyl } -acetic acid, (4- {4- [5- (1-methyl-1H-pyrazol-3-ylamino) -pyridin-2-yl ] -phenyl } -cyclohexyl) -acetic acid, (4- {4- [5- (5-fluoro-6-methoxy-pyridin-3-ylamino) -pyridin-2-yl ] -phenyl } -cyclohexyl) -acetic acid, (4- {5- [5- (6-trifluoromethyl-pyridin-3-ylamino) - Pyridin-2-yl ] -spirocyclohexyl subunit-1, 1' -indanyl } -acetic acid, (4- {4- [5- (benzooxazol-2-ylamino) -pyridin-2-yl ] -phenyl } -cyclohexyl) -acetic acid, 4- (4- {4- [2- (3-chlorophenylamino) -oxazol-5-yl ] -phenyl } -cyclohexyl) -butyric acid, (4- {4- [5- (6-trifluoromethyl-pyridin-3-ylamino) -pyridin-2-yl ] -phenyl } -cyclohexyl) -acetic acid, (6- {4- [4- (2H-tetrazol-5-ylmethyl) -cyclohexyl ] -phenyl } - Pyridazin-3-yl) - (6-trifluoromethyl-pyridin-3-yl) -amine, 3- (4- {4- [6- (6-trifluoromethyl-pyridin-3-ylamino) -pyridazin-3-yl ] -phenyl } -cyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one, (1- {4- [6- (3-trifluoromethyl-phenylamino) -pyridazin-3-yl ] -phenyl } -piperidin-4-yl) -acetic acid, (4- {4- [ 4-methyl-6- (6-trifluoromethyl-pyridin-3-ylamino) -pyridazin-3-yl ] -phenyl } -cyclohex-enyl } -cyclohexane -acetic acid, (4- {4- [5- (6-trifluoromethyl-pyridin-3-ylamino) -pyrazin-2-yl ] -phenyl } -cyclohexyl) -acetic acid, 6- [5- (4-chloro-phenyl) - [1,3,4] oxadiazol-2-yl ] -2- (2, 6-dichloro-phenyl) -1H-benzimidazole, 6- (5-cyclohexyl- [1,3,4] oxadiazol-2-yl) -2- (2, 6-dichloro-phenyl) -1H-benzimidazole, 6- (5-butyl- [1,3,4] oxadiazol-2-yl) -2- (2, 6-dichloro-phenyl) -1H-benzimidazole, 2- (2, 6-dichloro-phenyl) -6- [5- (5-methyl-pyridin-3-yl) - [1,3,4] oxadiazol-2-yl ] -1H-benzimidazole, 6- [5- (4-chloro-phenyl) - [1,3,4] oxadiazol-2-yl ] -2- (2, 6-dimethyl-4-morpholin-4-yl-phenyl) -1H-benzimidazole, 6- [5- (4-chloro-phenyl) - [1,3,4] oxadiazol-2-yl ] -2- (3, 5-dichloro-pyridin-4-yl) -1H-benzimidazole, 3- (4- {5- [5- (4-methoxy-phenyl) - [1,3,4] oxadiazol-2-yl ] -1H-benzimidazol-2-yl } -3, 5-dimethyl-phenyl) -2, 2-dimethyl-propionic acid, 3- (4- {6- [5- (4-methoxy-phenyl) - [1,3,4] oxadiazol-2-yl ] -1H-benzimidazol-2-yl } -3, 5-dimethyl-phenyl) -propionic acid, 3- (4- {6- [5- (4-methoxyphenyl-amino) - [1,3,4] oxadiazol-2-yl ] -1H-benzimidazol-2-yl } -3, 5-dimethylphenyl) -propionic acid, [3- (4- {6- [5- (4-chloro-phenyl) - [1,3,4] oxadiazol-2-yl ] -1H-benzimidazol-2-yl } -3, 5-dimethyl-phenyl) -propyl ] -phosphonic acid, 2- (2, 6-dichloro-phenyl) -6- (4, 5-diphenyl-oxazol-2-yl) -1H-benzimidazole, (4- {6- [5- (4-chloro-phenyl) - [1,3,4] oxadiazol-2-yl ] -1H-benzimidazol-2-yl } -3, 5-dimethyl-phenoxy) -acetic acid, 2- (2, 6-dichloro-phenyl) -6- (5-pyrrolidin-1-yl- [1,3,4] oxadiazol-2-yl) -1H-benzimidazole, and 3, 5-dimethyl-4- {6- [5- (4-trifluoromethyl-phenylamino) - [1,3,4] oxadiazol-2-yl ] -1H-benzimidazol-2-yl } -phenol.

A non-limiting example of a nimorac 1-like 1(NPC1-L1) inhibitor that may be used in combination with a compound of the present disclosure is ezetimibe.

Apolipoprotein A-I is a protein encoded by the APOA1 gene in humans. It has a specific role in lipid metabolism. Apolipoprotein A-I is the major protein component of High Density Lipoprotein (HDL) in plasma. Chylomicrons secreted by intestinal cells also contain ApoA-I, but rapidly migrate to HDL in the blood. The protein promotes the efflux of cholesterol from the tissue to the liver for secretion. It is a cofactor for Lecithin Cholesterol Acyltransferase (LCAT), which is responsible for the formation of most plasma cholesterol esters. Infusion of the apoA-I variant into humans has been shown to regress atherosclerotic plaques as assessed by intravascular ultrasound; thus, apoA-I reduces CVD risk and has the ability to slow progression and induce regression of atherosclerosis. A non-limiting example of an apoA-I up-regulator/inducer is RVX 208.

The ATP-binding cassette transporter ABCA1 (member 1 of the human transporter subfamily ABCA), also known as Cholesterol Efflux Regulator (CERP), is a protein encoded by the ABCA1 gene in humans. This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis. A non-limiting example of an ABCA1 modulator is probucol. Probucol reduces cholesterol levels in the blood by increasing the rate of LDL catabolism. In addition, probucol may inhibit cholesterol synthesis and delay cholesterol absorption. Probucol is a powerful antioxidant that inhibits the oxidation of cholesterol in LDL; this slows down the formation of foam cells that contribute to atherosclerotic plaques.

Liver X Receptors (LXRs) are members of the nuclear receptor family of transcription factors and are closely related to nuclear receptors such as PPAR, FXR and RXR. Liver X Receptors (LXRs) are important regulators of cholesterol, fatty acid and glucose homeostasis. LXR agonists are effective in treating murine models of atherosclerosis, diabetes, anti-inflammation and alzheimer's disease. Treatment with LXR agonists, including but not limited to hypocholesterolamide (hypocholenamide), T0901317, GW3965, or N, N-dimethyl-3- β -hydroxy-cholestyramide (DMHCA), reduces serum and liver cholesterol levels and inhibits the development of atherosclerosis in murine disease models. Examples of LXR agonists include, but are not limited to, GW3965 (synthetic non-steroidal Liver X Receptor (LXR) agonist/activator) and T0901317 (dual LXR, FXR agonists).

Farnesoid X Receptor (FXR), also known as NR1H4 (nuclear receptor subfamily 1, group H, member 4), is a nuclear hormone receptor that has activity similar to other steroid receptors (e.g., estrogen or progestin), but is more similar in form to PPAR, LXR and RXR. Activation of the nuclear receptor FXR is known to improve hyperglycemia and hyperlipidemia. A non-limiting example of an FXR agonist is GW4064(3- (2, 6-dichlorophenyl) -4- (3' -carboxy-2-chlorostilben-4-yl) oxymethyl-5-isopropylisoxazole).

Phospholipid transfer protein (PLTP) is a protein encoded in humans by the PLTP gene. The protein encoded by this gene is one of at least two lipid transfer proteins found in human plasma, CETP being the other. The encoded protein transfers phospholipids from triglyceride-rich lipoproteins to HDL. In addition to regulating the size of HDL particles, this protein may also be involved in cholesterol metabolism. It has been found that the gene has at least two transcript variants encoding different isoforms. Since PLTP affects both triglyceride-rich lipoprotein and HDL metabolism, modulation of this transfer protein has the potential to alter the risk of cardiovascular disease.

The fish oil is derived from the tissue of oily fish. Fish oils contain the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are precursors of eicosanoids known to have many health benefits. It is strongly recommended to use fish oil and other omega-3 sources in the following cases: hypertriglyceridemia, secondary cardiovascular disease and preventing hypertension. For example,

used with low-fat and low-cholesterol diets, very high triglycerides (fats) in the blood can be reduced. Examples of omega-3 fatty acids that can be used in combination with the compounds of the present disclosure include, but are not limited to

And

(eicosapentaenoic acid (icosapent ethyl)).

Examples of anti-diabetic agents that may be used in combination with the compounds of the present disclosure include, but are not limited to, insulin derivatives and mimetics; and insulin secretagogues, such as sulfonylureas; insulinotropic sulfonylurea receptor ligands, such as meglitinide, e.g., nateglinide and repaglinide; inhibitors of protein tyrosine phosphatase-1B (PTP-1B), including but not limited to PTP-112; inhibitors of GSK3 (glycogen synthase kinase-3), including but not limited to SB-517955, SB-4195052, SB-216763, NN-57-05441, and NN-57-05445; RXR ligands including, but not limited to, GW-0791 and AGN-194204; sodium-dependent glucose co-transporter inhibitors, including but not limited to T-1095; glycogen phosphorylase a inhibitors including, but not limited to, BAY R3401; biguanides including, but not limited to, metformin; alpha-glucosidase inhibitors, including but not limited to acarbose; GLP-1 (glucagon-like peptide-1), GLP-1 analogs including, but not limited to, toxin-specific exocrine peptide-4 (Exendin-4), and GLP-1 mimetics; and DPPIV (dipeptidyl peptidase IV) inhibitors, including but not limited to vildagliptin.

Examples of sulfonylureas include, but are not limited to, tolbutamide, chlorpropamide, tolazamide, acetylbenzenesulfonylcyclohexamide, 4-chloro-N- [ (1-pyrrolidinylamino) carbonyl ] -benzenesulfonamide (glipizide), glyburide (glyburide), gliclazide, 1-butyl-3-m-aminobenzenesulfonyl urea, carbutamide, glibornuride, glipizide, gliquidone, glimeperide, glithiazole, glibuzole (glibuzole), glihexanamide, gliopyrimidine, glimepiride, phenbutamide, imilare (amyl), and tolylcyclamide (tolcyclamide), or pharmaceutically acceptable salts thereof.

DPP-IV (dipeptidyl peptidase IV) is responsible for inactivating GLP-1. More particularly, DPP-IV produces GLP-1 receptor antagonists and thereby shortens the physiological response to GLP-1. GLP-1 is the major stimulator of insulin secretion from the pancreas and has a direct beneficial effect on glucose processing.

The DPP-IV inhibitor may be a peptide or preferably a non-peptide. Examples of DPP-IV inhibitors also include, but are not limited to, DPP-IV inhibitors disclosed generally and specifically in: WO 98/19998, DE 19616486 a1, WO 00/34241 and WO 95/15309 (in each case in particular in the compound claims), and the end products of the working examples, the subject matter of the end products, the pharmaceutical preparations and the claims are hereby incorporated by reference into the present application.

GLP-1 (glucagon-like peptide-1) is an insulinotropic protein, produced by W.E. Schmidt et al, in diabetes [ diabetes mellitus ]]28,1985,704-707 and in US 5,705,483. The term "GLP-1 agonist" includes GLP-1(7-36) NH₂Variants and analogs of (a), which are specifically disclosed in U.S.5,120,712, U.S.5,118666, U.S.5,512,549, WO 91/11457 and c.orskov, et al, j.biol.chem]264(1989) 12826. Additional examples include: GLP-1(7-37), wherein in GLP-1(7-36) NH₂Substitution of Gly for Arg at position 37 of the molecule³⁶The carboxy-terminal amide functional group of (A), and variants and analogs thereof, including GLN⁹-GLP-1(7-37)、D-GLN⁹GLP-1(7-37), acetylLYS⁹-GLP-1(7-37)、LYS¹⁸GLP-1(7-37), and in particular GLP-1(7-37) OH, VAL⁸-GLP-1(7-37)、GLY⁸-GLP-1(7-37)、THR⁸-GLP-1(7-37)、MET⁸GLP-1(7-37) and 4-imidazopropionyl-GLP-1. GLP agonist analogues are also particularly preferred: agonist peptide-4, described in Greig et al (in diabetes [ diabetes)]1999,42, 45-50).

Also included in the definition of "anti-diabetic agent" are insulin sensitivity enhancers which restore impaired insulin receptor function to reduce insulin resistance and thus enhance insulin sensitivity. Examples include hypoglycemic thiazolidinedione derivatives (e.g. glitazone, (S) - ((3, 4-dihydro-2- (phenyl-methyl) -2H-1-benzopyran-6-yl) methyl-thiazolidine-2, 4-dione (englitazone), 5- { [4- (3- (5-methyl-2-phenyl-4-oxazolyl) -1-oxapropyl) -phenyl ] -methyl } -thiazolidine-2, 4-dione (darlitazone), 5- { [4- (1-methyl-cyclohexyl) methoxy) -phenyl ] methyl } -thiazolidine-2, 4-dione (ciglitazone), 5- { [4- (2- (1-indolyl) ethoxy) phenyl ] methyl } -thiazolidine-2, 4-dione (DRF2189), 5- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) -ethoxy) ] benzyl } -thiazolidine-2, 4-dione (BM-13.1246), 5- (2-naphthylsulfonyl) -thiazolidine-2, 4-dione (AY-31637), bis {4- [ (2, 4-dioxo-5-thiazolidinyl) methyl ] phenyl } methane (YM268), 5- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) -2-hydroxyethoxy ] benzyl } -thiazolidine-2, 4-dione (AD-5075), 5- [4- (1-phenyl-1-cyclopropanecarbonylamino) -benzyl ] -thiazolidine-2, 4-dione (DN-108)5- { [4- (2- (2, 3-dihydroindol-1-yl) ethoxy) phenyl ] methyl } -thiazolidine-2, 4-dione, 5- [3- (4-chloro-phenyl) -2-propynyl ] -5-phenylsulfonyl) thiazolidine-2, 4-dione, 5- [3- (4-chlorophenyl) -2-propynyl ] -5- (4-fluorophenyl-sulfonyl) thiazolidine-2, 4-dione, 5- { [4- (2- (methyl-2-pyridinyl-amino) -ethoxy) phenyl ] methyl } -thiazolidine-2, 4-dione (rosiglitazone), 5- { [4- (2- (5-ethyl-2-pyridinyl) ethoxy) phenyl ] -methyl } thiazolidine-2, 4-dione (pioglitazone), 5- { [4- ((3, 4-dihydro-6-hydroxy-2, 5,7, 8-tetramethyl-2H-1-benzopyran-2-yl) methoxy) -phenyl ] -methyl } -thiazolidine-2, 4-dione (troglitazone), 5- [6- (2-fluoro-benzyloxy) naphthalen-2-ylmethyl ] -naphthalene H-thiazolidine-2, 4-dione (MCC555), 5- { [2- (2-naphthyl) -benzoxazol-5-yl ] -methyl } thiazolidine-2, 4-dione (T-174) and 5- (2, 4-dioxathiazolidin-5-ylmethyl) -2-methoxy-N- (4-trifluoromethyl-benzyl) benzamide (KRP 297)).

Examples of anti-obesity agents that may be used in combination with the compounds of the present disclosure include, but are not limited to, orlistat, sibutramine, phentermine, and cannabinoid receptor 1(CB1) antagonists, such as rimonabant.

Examples of peroxisome proliferator-activator receptor agonists that may be used in combination with the compounds of the present disclosure include, but are not limited to, fenofibrate, pioglitazone, rosiglitazone, ticagrelor, BMS-298585, L-796449, the compounds specifically described in patent application WO 2004/103995 (i.e., the compounds of examples 1 to 35 or the compounds specifically listed in claim 21), or the compounds specifically described in patent application WO 03/043985 (i.e. the compounds of examples 1 to 7 or the compounds specifically listed in claim 19) and especially (R) -1- {4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy ] -benzenesulfonyl } -2, 3-dihydro-1H-indole-2-carboxylic acid or its salts.

Examples of hypolipidemic agents that may be used in combination with the compounds of the present disclosure include, but are not limited to, HMG-CoA reductase inhibitors, squalene synthase inhibitors, LXR agonists, FXR agonists, fibrates, cholesterol absorption inhibitors, nicotinic acid bile acid binding resins, benpropedoic acid (bempedoic acid), nicotinic acid and other GPR109 agonists, and aspirin.

Examples of antihypertensive agents that may be used in combination with the compounds of the present disclosure include, but are not limited to, loop diuretics; angiotensin Converting Enzyme (ACE); inhibitors of the Na-K-ATP enzyme membrane pump; neutral Endopeptidase (NEP) inhibitors; ACE/NEP inhibitors; an angiotensin II antagonist; a renin inhibitor; a beta-adrenoceptor blocker; myogenic agents (inotropic agents); a calcium channel; an aldosterone receptor antagonist; and aldosterone synthase inhibitors.

Examples of loop diuretics that may be used in combination with the compounds of the present disclosure include, but are not limited to, ethacrynic acid, furosemide, and torasemide.

The term "ACE-inhibitor" (also known as angiotensin converting enzyme inhibitor) includes molecules that interrupt the enzymatic degradation of angiotensin I to angiotensin II. Such compounds are useful for regulating blood pressure and treating congestive heart failure. Examples include, but are not limited to, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat (enaprilat), fosinopril, imidapril, lisinopril, moexipril (moveltopril), perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril, or pharmaceutically acceptable salts thereof.

A non-limiting example of a Na-K-ATPase membrane pump inhibitor is digoxin.

The term "NEP inhibitor" refers to a compound that inhibits Neutral Endopeptidase (NEP). Examples include, but are not limited to, candesartan, dexecadotril, ecadotril, racecadotril, lapatrilat, fasidotril, olpadra, gemotrila, Daglutril (Daglutril), SCH-42495, SCH-32615, UK-447841, AVE-0848, PL-37, and (2R,4s) -5-biphenyl-4-yl-4- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester or pharmaceutically acceptable salts thereof. NEP inhibitors also include phosphine/biaryl substituted dipeptide derivatives, as disclosed in us patent 5,155,100. NEP inhibitors also include N-mercaptoacylphenylalanine derivatives as disclosed in PCT application WO 2003/104200. NEP inhibitors also include dual-effect antihypertensive agents, as disclosed in PCT applications WO 2008/133896, WO 2009/035543, or WO 2009/134741. Other examples include those described in U.S. application 12/788,794; 12/788,766, and 12/947,029. NEP inhibitors also include compounds disclosed in WO 2010/136474, WO 2010/136493, WO 2011/061271, WO 2012/065953, WO 2012/065956, WO 2014/126979, and WO 2014/015965. Further examples of NEP inhibitors are the compounds disclosed in WO 2015116786, WO 2015116760, WO 2014138053, WO 2014025891, WO 2013184934, WO 2013067163, WO 2012166389, WO 2012166387, WO 2012112742, and WO 2012082853.

The term "ACE/NEP inhibitor" refers to a compound that inhibits both Angiotensin Converting Enzyme (ACE) and Neutral Endopeptidase (NEP). Examples of ACE/NEP inhibitors that may be used in combination with the compounds of the present disclosure include, but are not limited to, olpadra, lapachador, and fasidotril.

Angiotensin II antagonists or AT₁The class of receptor antagonists includes compounds having different structural characteristics, with non-peptide compounds being substantially preferred. Examples of angiotensin II antagonists that may be used in combination with the compounds of the present disclosure include, but are not limited to, valsartan, losartan, candesartan, eprosartan, irbesartan, saprisartan, tasosartan, telmisartan, the names having the following formulae E-1477 and ZD-8731 Compounds

Or in each case, a pharmaceutically acceptable salt thereof.

The term "renin inhibitor" includes ditekiren (chemical name: [1S- [1R,2R,4R (1R,2R) ] ] -1- [ (1, 1-dimethylethoxy) carbonyl ] -L-prolyl L-phenylalanyl-N- [ 2-hydroxy-5-methyl-1- (2-methylpropyl) -4- [ [ [ 2-methyl-1- [ [ (2 pyridylmethyl) amino ] carbonyl ] butyl ] amino ] carbonyl ] hexyl ] -N- α -methyl-L-histidinamide); telagkiren (terakiren) (chemical name: [ R- (R, S) ] -N- (4-morpholinylcarbonyl) -L-phenylalanyl-N- [1- (cyclohexylmethyl) -2-hydroxy-3- (1-methylethoxy) -3-oxapropyl ] -S-methyl-L-cysteamine amide); aliskiren (Aliskiren) (chemical name: (2S,4S,5S,7S) -5-amino-N- (2-carbamoyl-2, 2-dimethylethyl) -4-hydroxy-7- { [ 4-methoxy-3- (3-methoxypropoxy) phenyl ] methyl } -8-methyl-2- (propan-2-yl) nonanamide) and zankiren (zankiren) (chemical name: [1S- [1R [ R (R) ],2S,3R ] ] -N- [1- (cyclohexylmethyl) -2, 3-dihydroxy-5-methylhexyl ] -alpha- [ [2- [ [ (4-methyl-1-piperazinyl) sulfonyl ] methyl ] -1-oxo-3-phenylpropyl ] -amino ] -4-thiazolopropionamide) or a hydrochloride salt thereof, or SPP630, SPP635 and SPP800 developed by Speedel, or RO 66-1132 and RO 66-1168 having the formulae (a) and (B):

Or a pharmaceutically acceptable salt thereof. The term "aliskiren", if not defined specifically, is to be understood as the free base and salts thereof, especially pharmaceutically acceptable salts thereof, most preferably the hemi-fumarate salt thereof.

Examples of beta-adrenergic receptor blockers that can be used in combination with the compounds of the present disclosure include, but are not limited to, acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol, and timolol.

Examples of myotonics that can be used in combination with the compounds of the present disclosure include, but are not limited to, digoxin, dobutamine, and milrinone; inotropes, as used herein, include, for example, dobutamine, isoproterenol, milrinone, amrinone, levosimendan, epinephrine, norepinephrine, isoproterenol, and digoxin.

Examples of calcium channel blockers that can be used in combination with the compounds of the present disclosure include, but are not limited to, amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine, and verapamil.

Aldosterone synthase inhibitors include steroidal and non-steroidal aldosterone synthase inhibitors, the latter being most preferred. The class of aldosterone synthase inhibitors includes compounds having different structural characteristics. Examples of aldosterone synthase inhibitors that can be used in combination with a compound of the present disclosure include, but are not limited to, the (+) -enantiomer of fadrozole hydrochloride having the formula (U.S. Pat. Nos. 4,617,307 and 4,889,861)

Or, if applicable, a pharmaceutically acceptable salt thereof; and compounds and analogues generally and specifically disclosed in, for example, US 2007/0049616 (particularly in the compound claims), and the end products of the working examples, the subject matter of the end products, pharmaceutical formulations and claims are hereby incorporated by reference into this application. Examples of aldosterone synthase inhibitors that may be used in combination with the compounds of the present disclosure include, but are not limited to, 4- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-5-yl) -3-methylbenzonitrile; 5- (2-chloro-4-cyanophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazole-5-carboxylic acid (4-methoxybenzyl) methylamide; 4' -fluoro-6- (6,7,8, 9-tetrahydro-5H-imidazo [1,5-a ] azepin-5-yl) biphenyl-3-carbonitrile; 5- (4-cyano-2-methoxyphenyl) -6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazole-5-carboxylic acid butyl ester; 4- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-5-yl) -2-methoxybenzonitrile; 4-fluorobenzyl 5- (2-chloro-4-cyanophenyl) -6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazole-5-carboxylate; 5- (4-cyano-2-trifluoromethoxyphenyl) -6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazole-5-carboxylic acid methyl ester; 2-isopropoxyethyl 5- (4-cyano-2-methoxyphenyl) -6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazole-5-carboxylate; 4- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-5-yl) -2-methylbenzonitrile; 4- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-5-yl) -3-fluorobenzonitrile; 4- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-5-yl) -2-methoxybenzonitrile; 3-fluoro-4- (7-methylene-6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-5-yl) benzonitrile; cis-3-fluoro-4- [7- (4-fluoro-benzyl) -5,6,7, 8-tetrahydro-imidazo [1,5-a ] pyridin-5-yl ] benzonitrile; 4' -fluoro-6- (9-methyl-6, 7,8, 9-tetrahydro-5H-imidazo [1,5-a ] azepin-5-yl) biphenyl-3-carbonitrile; 4' -fluoro-6- (9-methyl-6, 7,8, 9-tetrahydro-5H-imidazo [1,5-a ] azepin-5-yl) biphenyl-3-carbonitrile, or in each case the (R) or (S) enantiomer thereof; or, if applicable, a pharmaceutically acceptable salt thereof.

The term aldosterone synthase inhibitor also includes, but is not limited to, compounds and analogs disclosed in WO 2008/076860, WO 2008/076336, WO 2008/076862, WO 2008/027284, WO 2004/046145, WO 2004/014914, and WO 2001/076574.

In addition, aldosterone synthase inhibitors also include, but are not limited to, compounds and analogs disclosed in U.S. patent applications US 2007/0225232, US 2007/0208035, US 2008/0318978, US 2008/0076794, US 2009/0012068, US 20090048241, and PCT applications WO 2006/005726, WO 2006/128853, WO 2006128851, WO 2006/128852, WO 2007065942, WO 2007/116099, WO 2007/116908, WO 2008/119744, as well as european patent application EP 1886695. Preferred aldosterone synthase inhibitors suitable for use in the present disclosure include, but are not limited to, 8- (4-fluorophenyl) -5, 6-dihydro-8H-imidazo [5,1-c1[1,41 oxazine; 4- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-8-yl) -2-fluorobenzonitrile; 4- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-8-yl) -2, 6-difluorobenzonitrile; 4- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-8-yl) -2-methoxybenzonitrile; 3- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-8-yl) benzonitrile; 4- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-8-yl) phthalonitrile; 4- (8- (4-cyanophenyl) -5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-8-yl) benzonitrile; 4- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-8-yl) benzonitrile; 4- (5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazin-8-yl) naphthalene-1-carbonitrile; 8- [4- (1H-tetrazol-5-yl) phenyl 1-5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazine as developed by Speedel or in each case, the (R) or (S) enantiomer thereof; or, if applicable, a pharmaceutically acceptable salt thereof.

Aldosterone synthase inhibitors useful in said combination include, but are not limited to, compounds and analogues as disclosed in general and in particular in e.g. WO 2009/156462 and WO 2010/130796, in particular in the compound claims, as well as the end products of the working examples, the subject matter of the end products, pharmaceutical preparations and claims. Preferred aldosterone synthase inhibitors suitable for use in the present disclosure include 3- (6-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl) -benzonitrile hydrochloride, 1- (4-methanesulfonyl-benzyl) -3-methyl-2-pyridin-3-yl-1H-indole, 2- (5-benzyloxy-pyridin-3-yl) -6-chloro-1-methyl-1H-indole, 5- (3-cyano-1-methyl-1H-indol-2-yl) -nicotinic acid ethyl ester, N- [5- (6-chloro-3-cyano-1-methyl-1H-indol-2-yl) -2-yl) -pyridin-3-ylmethyl ] -ethanesulfonamide, pyrrolidine-1-sulfonic acid 5- (6-chloro-3-cyano-1-methyl-1H-indol-2-yl) -pyridin-3-yl ester, N-methyl-N- [5- (1-methyl-1H-indol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide, 6-chloro-1-methyl-2- {5- [ (2-pyrrolidin-1-yl-ethylamino) -methyl ] -pyridin-3-yl } -1H-indole-3-carbonitrile, 6-chloro-2- [5- (4-methanesulfonyl-piperazin-1-ylmethyl) -pyridin-3-yl ] -1-methyl-1H-indole-3-carbonitrile, 6-chloro-1-methyl-2- {5- [ (1-methyl-piperidin-4-ylamino) -methyl ] -pyridin-3-yl } -1H-indole-3-carbonitrile, morpholine-4-carboxylic acid [5- (6-chloro-3-cyano-1-methyl-1H-indol-2-yl) -pyridin-3-ylmethyl ] -amide, N- [5- (6-chloro-1-methyl-1H-indole Indol-2-yl) -pyridin-3-ylmethyl ] -ethanesulfonamide, C, C, C-trifluoro-N- [5- (1-methyl-1H-indol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide, N- [5- (3-chloro-4-cyano-phenyl) -pyridin-3-yl ] -4-trifluoromethyl-benzenesulfonamide, N- [5- (3-chloro-4-cyano-phenyl) -pyridin-3-yl ] -1-phenyl-methanesulfonamide, N- (5- (3-chloro-4-cyanophenyl) pyridin-3-yl) butane-1-sulfonamide, n- (1- (5- (4-cyano-3-methoxyphenyl) pyridin-3-yl) ethyl) ethanesulfonamide, N- ((5- (3-chloro-4-cyanophenyl) pyridin-3-yl) (cyclopropyl) methyl) ethanesulfonamide, N- (cyclopropyl (5- (1H-indol-5-yl) pyridin-3-yl) methyl) ethanesulfonamide, N- (cyclopropyl (5-naphthalen-1-yl-pyridin-3-yl) methyl) ethanesulfonamide, ethanesulfonic acid [5- (6-chloro-1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl) -pyridin-3-ylmethyl ] -amide, and ethanesulfonic acid { [5- (3-chloro-1-methyl-1H-pyrrolo [2,3-b ] pyridin-2-yl) -pyridin-3-ylmethyl ] -amide -4-cyano-phenyl) -pyridin-3-yl ] -cyclopropyl-methyl } -ethyl-amide.

Lipid lowering agents are known in The art and are described, for example, in The Pharmacological Basis of Therapeutics [ pharmacology of Therapeutics ], 11 th edition, Brunton, Lazo and Parker, editors, McGraw-Hill (2006); 2009 Physicians' Desk Reference (PDR), e.g., in 63 rd edition (2008), Thomson PDR.

"combination therapy" is intended to include the administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time and in any order, or in an alternating manner and in any order, as well as the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule or multiple single capsules for each therapeutic agent with a fixed ratio. Sequential or substantially simultaneous administration of each therapeutic agent may be by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent of a selected combination may be administered by intravenous injection, while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The order of administration of the therapeutic agents is not critical.

In accordance with the foregoing, the present disclosure also provides a therapeutic combination, e.g., a kit, kit of parts, e.g., for use in any method defined herein, comprising a compound having formula (I), or a pharmaceutically acceptable salt thereof, for simultaneous or sequential use with at least one pharmaceutical composition comprising at least one therapeutic agent selected from: a hypolipidemic agent, niacin or an analog thereof, a bile acid sequestrant, a thyroid hormone mimetic, a Thyroid Hormone Receptor (THR) β -selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl CoA diacylglycerol acyltransferase (DGAT) inhibitor, a niemann pick C1-like 1(NPC1-L1) inhibitor, an agonist of ATP-binding cassette (ABC) protein G5 or G8, an inhibitory nucleic acid targeting PCSK9, an inhibitory nucleic acid targeting apoB100, an apoA-I up-regulator/inducer, an ABCA1 stabilizer or inducer, a phospholipid transfer protein (PLTP) inhibitor, a fish oil, an anti-diabetic agent, an anti-obesity agent, a peroxisome proliferator activator receptor agonist, an ATP Citrate Lyase (ACL) inhibitor, and an anti-hypertensive agent, or a pharmaceutically acceptable salt thereof. The kit may include instructions for its administration. The combination may be a fixed combination (e.g. in the same pharmaceutical composition) or a free combination (e.g. in separate pharmaceutical compositions).

Similarly, the present disclosure provides a kit comprising: (i) a pharmaceutical composition of the present disclosure; and (ii) a pharmaceutical composition comprising a compound selected from the group consisting of: hypolipidemic agents, niacin or analogs thereof, bile acid sequestrants, thyroid hormone mimetics, Thyroid Hormone Receptor (THR) beta-selective agonists, microsomal triglyceride transfer protein (MTP) inhibitors, acyl CoA: diacylglycerol acyltransferase (DGAT) inhibitors, Niemann Pic C1-like 1(NPC1-L1) inhibitors, agonists of ATP-binding cassette (ABC) protein G5 or G8, inhibitory nucleic acids targeting PCSK9, inhibitory nucleic acids targeting apoB100, apoA-I up-regulators/inducers, ABCA1 stabilizers or inducers, phospholipid transfer protein (PLTP) inhibitors, fish oils, anti-diabetic agents, anti-obesity agents, peroxisome proliferator activator receptor agonists, ATP Citrate Lyase (ACL) inhibitors, and anti-hypertensive agents, or a pharmaceutically acceptable salt thereof, components (i) to (ii) being in the form of two separate units.

Likewise, the present disclosure provides a method as defined above comprising co-administration, e.g., concurrently or sequentially, of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, with a second drug substance that is: hypolipidemic agents, niacin or analogs thereof, bile acid sequestrants, thyroid hormone mimetics, Thyroid Hormone Receptor (THR) beta-selective agonists, microsomal triglyceride transfer protein (MTP) inhibitors, acyl CoA diacylglycerol acyltransferase (DGAT) inhibitors, niemann-pick C1-like 1(NPC1-L1) inhibitors, agonists of ATP-binding cassette (ABC) protein G5 or G8, inhibitory nucleic acids targeting PCSK9, inhibitory nucleic acids targeting apoB100, apoA-I upregulators/inducers, ABCA1 stabilizers or inducers, phospholipid transfer protein (PLTP) inhibitors, fish oils, anti-diabetic agents, anti-obesity agents, peroxisome proliferator activator receptor agonists, ATP Citrate Lyase (ACL) inhibitors, and anti-hypertensive agents, for example as set forth above.

Examples of the invention

The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the disclosure to the particular procedures described herein. It should be understood that these examples are provided for the purpose of illustrating certain embodiments, and are not intended to limit the scope of the present disclosure thereby. It is further understood that various other embodiments, modifications, and equivalents may be resorted to, falling within the spirit of the disclosure and/or the scope of the appended claims.

Analytical methods, materials and apparatus

Reagents and solvents received from commercial suppliers were used unless otherwise indicated. Proton Nuclear Magnetic Resonance (NMR) spectra were obtained on either a Bruker or Varian spectrometer at 300MHz or 400 MHz. The spectra are given in ppm (δ) and the coupling constant J is reported in hertz. Tetramethylsilane (TMS) was used as an internal standard.

Abbreviations

The purification method comprises the following steps:

the final product was purified by preparative reverse phase HPLC using a Waters XBridge prep C18 OBD column, 5 μm, 30mm x250mm, part No. 186004025. The following mobile phases were used:

Eluent a: h₂0.1% TFA in O and eluent B: ACN

Eluent a: h₂0.01M HCl in O and eluent B: ACN

The gradient is designed according to the specific requirements of the separation problem. The pure product is obtained from ACN/H₂Lyophilized in O and obtained as the free base or the corresponding trifluoroacetate, formate or hydrochloride salt, depending on the eluent used. In some cases, the salt form is altered using the following method:

the TFA salt in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2X) and brine washes over Na₂SO₄Dried, filtered and evaporated to dryness in vacuo. Dissolving the residue in ACN/H₂O (1:1) and 1M HCl (about 1.5-3 equivalents per basic center) and then lyophilized to give the product as the hydrochloride salt as a white solid.

The analysis method comprises the following steps: the product was analyzed by the following analytical method.

Example 1: general synthetic procedure for assembling tetramer Compounds

As shown in the above synthetic schemes, cyclic and linear tetrameric compounds (e.g., compound 86 in example 2) are assembled on solid phase and in solution from blocks a (succinate), B (diamine), C (α -amino acid (α -aa)), D (α -amino acid (α -aa)), and E (aldehyde). The synthesis of building blocks A-E for synthesis is described below. The letters that build the blocks indicate specific positions in the final compound. For the solid phase strategy, PS-2-chlorotrityl chloride resin was used. Various coupling agents are used to form amides, such as HATU, PyOxim, TBTU, DMT-MM and Gaussez's reagent (1-chloro-N, N, 2-trimethyl-1-propenylamine).

Succinate A is coupled with diamine B using standard coupling conditions (e.g., amide coupling reagents in solvent) followed by removal of the Fmoc protecting group under basic conditions to afford A-B. Polymer-bound dimers A-B were obtained by: the building block a-B is attached to a solid Phase (PS) by coupling the acid groups on a of the building block a-B with amines on the resin using standard coupling conditions (e.g., amide coupling reagents in solvent), followed by deprotection of the amines on B of the building block a-B (e.g., removal of the F-moc protecting group under basic conditions or removal of the Boc protecting group under acidic conditions). The deprotection and coupling steps are repeated, followed by cleavage from the resin (e.g., by treatment with HFIP) to provide intermediates A-B-C-D. Reductive amination of intermediate A-B-C-D with aldehyde E using a reducing agent such as sodium cyanoborohydride or sodium borohydride in a solvent provides intermediate A-B-C-D-E. Cyclization using an amide coupling reagent under standard coupling conditions followed by deprotection provides cyclic tetrameric compounds.

Example 2: synthesis of building Block A-succinate

Example 2.1: synthesis of (R) -2-benzyl-4- (tert-butoxy) -4-oxobutanoic acid (A1)

Step 1.(S) -4-benzyl-3- (3-phenylpropionyl) oxazolidin-2-one (A1-3)

To a stirred solution of (S) -4-benzyloxazolidin-2-one (a1-2, 500g, 2.821mol) in THF (9L) was added n-BuLi (2.5M in hexane) (1.24L, 3.103mol) over a period of 30 minutes at-78 ℃. The reaction mixture was then stirred at-78 ℃ for 30 minutes and a solution of 3-phenylpropionyl chloride (A1-1, 571g, 3.38mol) in THF (1L) was added over a period of 1 hour at-78 to-60 ℃. The resulting mixture was stirred for 2 hours and then allowed to warm slowly to room temperature. The reaction mixture was cooled to 0 ℃ with saturated NH₄Aqueous Cl (500mL) was quenched and the product was extracted with DCM (2 × 1.5l). The combined organic phases were washed with 0.5N NaOH (1L) and brine (1L) over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was triturated with petroleum ether (5L) for 1 hour and the resulting suspension was filtered. The residue was washed with petroleum ether (500mL) and dried under vacuum to give compound a1-1 as an off-white solid (815g, 93%). Analytical method 7; t is t_R＝1.53min；[M+H]⁺＝310.2。

Step 2.(R) -tert-butyl 3-benzyl-4- ((S) -4-benzyl-2-oxooxazolidin-3-yl) -4-oxobutanoate (A1-5)

To a stirred solution of A1-3(500g, 1.616mol) in THF (7L) at-78 deg.C was added 1M NaHMDS (1.94L, 1.939mol) in THF over a period of 30 minutes. The reaction mixture was then stirred at-78 ℃ for 1 hour and a solution of tert-butyl 2-bromoacetate (A1-4, 472.8g, 2.424mol) in THF (500mL) was added dropwise over a period of 30 minutes at-78 ℃. The resulting mixture was stirred for 2 hours and then saturated NH was used ₄Aqueous Cl (500 mL). The product was extracted with EtOAc (2X 1.5L). The combined organic phases were washed with brine (2L) and Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was triturated with methanol (800mL) for 1 hour. The suspension was filtered and the resulting residue was washed with methanol (200mL) and dried under vacuum to give intermediate a1-5(410g, 60%) as an off-white solid. Analytical method 7; t is t_R＝1.78min；[M-tBu+H]⁺＝368.3。

Step 3.(R) -2-benzyl-4- (tert-butoxy) -4-oxobutanoic acid (A1)

To a stirred solution of A1-5(250g, 0.59mol) in THF (9L) at 0-5 deg.C was added 30% H₂O₂(267mL, 2.37 mol). The resulting mixture was stirred at 0-5 ℃ for 30 minutes, and then LiOHH was added₂O (49.5g, 1.18mol) in H₂Solution in O (3L). The reaction mixture was stirred at 0-5 ℃ for 1 hour and then quenched by the addition of saturated aqueous sodium sulfite (1.6L) and saturated sodium bicarbonate (1.6L). The resulting mixture was concentrated in vacuo (THF removed). Addition of H₂O (3L) and the aqueous phase was washed with DCM (2 × 1L) to remove any impurities. The aqueous phase was cooled to 5 ℃ and acidified to pH about 1.5 with 6M HCl (1L). The aqueous phase was extracted with ethyl acetate (3 × 1L). The combined organic phases were washed with brine (1L) and Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave intermediate a1(125g, 82%) as oil. Analytical method 7; t is t _R＝1.78min；[M-H]^-＝263.5。¹H NMR (400MHz, chloroform-d) d ppm 1.42(s,9H),2.36(dd, J ═ 16.93,4.58Hz,1H),2.48-2.62(m,1H),2.71-2.83(m,1H),3.00-3.18(m,2H),7.12-7.35(m, 6H).

The following Building Blocks (BB) in table 1 were synthesized according to the method described for building block a1 in example 2.1.

Table 1: succinate-building Block A

Example 2.2: synthesis of (S) -4-benzyl-3- (3- (pyridin-3-yl) propionyl) oxazolidin-2-one (A2-1)

To 3- (pyridin-3-yl) propionic acid (7.56g, 50mmol), (S) -4-benzyloxazolidin-2-one (8.86g, 50.0mmol) and DMAP (1.833g, 15.0mmol) was added DCM (150mL) and the resulting mixture was stirred at room temperature for 20min, then cooled to 0 ℃. The acid is not dissolved to a great extent. A solution of DIC (10.91mL, 70.0mmol) in DCM (10mL) was then added dropwise at 0 ℃. However, the acid is still only partially dissolved. DMF (75mL) was added and the mixture was stirred for 20.5 hours and then warmed to room temperature. The solution was concentrated to dryness in vacuo and the residue was suspended in DCM. The suspension was filtered and the residue was washed with DCM. The filtrate was concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: heptane/DIEA (98: 2); eluent B: EtOAc/DIEA (98: 2)). The pure fractions were combined and concentrated to dryness in vacuo, and the residue was dissolved in toluene and the solution was concentrated to dryness in vacuo. This treatment was repeated twice. Obtain oil and crystal A2-1(11.56g, 37.3mmol, 75% yield) of the mixture of bodies. An analytical method 10; t is t_R＝0.77min；[M+H]⁺＝311.1。

The following intermediates (Int) or Building Blocks (BB) in Table 2 were synthesized according to the method described for intermediate A2-1 in example 2.2

Table 2:

example 2.3: synthesis of 2- (3, 3-dimethyl-2, 3-dihydro-1H-inden-1-yl) acetic acid (A5-2)

Step 1 benzyl 2- (3-oxo-2, 3-dihydro-1H-inden-1-yl) acetate (A5-1)

To 2- (3-oxo-2, 3-dihydro-1H-inden-1-yl) acetic acid (3.80g, 20.0mmol) and K₂CO₃(2.76g, 20.00mmol) DMF (50mL) and benzyl bromide (2.379mL, 20.00mmol) were added. The reaction was stirred at room temperature for 15 h, then in EtOAc (300mL) and 5% NaHCO₃(250mL) partitioned between aqueous solutions. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 50mL) and brine (30mL) were washed over Na₂SO₄Drying, filtration, and concentration to dryness in vacuo gave A5-1(5.66g, 20.0mmol, ca. 100% yield) as a beige oil. The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.06min；[M+H]⁺＝281.2。

Step 2.2- (3, 3-dimethyl-2, 3-dihydro-1H-inden-1-yl) acetic acid (A5-2)

Step 2-1: at-40 ℃ to TiCl₄(1.103mL, 10.00mmol) in DCM (25mL) was slowly added 2M dimethylzinc in toluene (7.50mL, 15.00 mmol). After stirring for 10 min at-40 deg.C, A5-1(1402mg, 5.0mmol) in DCM (5mL) was added The solution of (1). The resulting solution was stirred for 8 hours and then slowly warmed to 0 ℃. Stirring was continued for 13.5 hours and the reaction was allowed to warm to room temperature. By addition of H₂The reaction was quenched with O (2mL) and MeOH (2 mL). Addition of H₂O (10mL) and DCM (10mL) and the phases were separated. The organic phase is treated with H₂O (10mL) and brine (10mL) were washed, then concentrated to dryness in vacuo.

Step 2-2: to the crude residue of step 2-1 dissolved in dioxane (20mL) and MeOH (5mL) was added 1M NaOH (10.0mL, 10.0mmol) and the resulting mixture was stirred at room temperature for 2 hours to a clear solution. Dioxane and MeOH were removed in vacuo, and the residue was partitioned between EtOAc (100mL) and 1M aqueous HCl (20 mL). Mixing the organic phase with 5% KHSO₄Aqueous (2 × 20mL) and brine (15mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: heptane/AcOH (99: 1); eluent B: EtOAc/AcOH (99: 1)). The pure fractions were combined and concentrated to dryness in vacuo. The residue was dissolved in toluene and concentrated to dryness in vacuo. This treatment was repeated twice to give A5-2 as a pale yellow solid (769mg, 3.76mmol, 75% yield). The product was used in the next step without further purification. An analytical method 10; t is t _R＝1.00min；[M-H]^-＝203.2。

Example 2.4: synthesis of (S) -4-benzyl-3- (2- ((1R,3S) -3-methyl-2, 3-dihydro-1H-inden-1-yl) acetyl) oxazolidin-2-one (A6-6)

Step 1.(S) -3-methyl-2, 3-dihydro-1H-inden-1-one (A6-1)

Step 1-1: to a solution of (S) -3-phenylbutyric acid (5.0mL, 32.6mmol) in DCM (30mL) was added SOCl₂(9.50mL, 130mmol) and DMF (0.252mL, 3.26 mmol). The resulting mixture was stirred at room temperature for 110 minutes, then at 45 ℃ for 30 minutes, then concentrated to dryness in vacuo (40 ℃, about 90 mbar).

Step 1-2: to the crude product of step 1-1 in DCM (30mL) at 0 deg.CIn 20 minutes, add AlCl in portions₃(8.68g, 65.1 mmol). The resulting mixture was stirred at 0 ℃ for 45 minutes and then poured onto ice. The phases were separated and the aqueous phase was extracted with DCM (60 mL). The combined organic phases were washed with 5% KHSO₄Aqueous solution (20mL) and brine (20mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The residue was dissolved in DCM and purified by flash chromatography on silica gel (38 mm diameter, 25g of silica gel 60(0.032mm-0.063 mm); eluting with DCM (ca. 200 mL)). The fractions containing the product were collected and concentrated in vacuo (30 ℃, ca. 80mbar) to give A6-1 as a yellow oil (assumed to be 32.6 mmol). An analytical method 10; t is t _R＝0.84min；[M+H]⁺＝147.0。

Step 2.(1R,3S) -3-methyl-2, 3-dihydro-1H-inden-1-ol (A6-2)

To a solution of A6-1(4.82g, 32.6mmol) in MeOH (100mL) at 0 deg.C was added NaBH₄(1.499g, 39.6mmol) and the resulting mixture stirred at 0 ℃ for 1 hour and then by addition of 5% NaHCO₃(5mL) aqueous solution and H₂O (10mL) quench. MeOH was removed in vacuo and the resulting residue was taken up in EtOAc (100mL) and 5% NaHCO₃(15mL) partitioned between aqueous solutions. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 10mL) and brine (10mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo (30 ℃ C.; 65mbar) gave A6-2 as a white solid (4.645g, 31.3mmol, 96% yield). The crude product was used in the next step. An analytical method 15; t is t_R＝3.28min；[M-OH]⁺＝131.1。

Step 3.(1S,3S) -1-allyl-3-methyl-2, 3-dihydro-1H-indene (A6-3)

To a solution of A6-2(4.64g, 31.3mmol) and allyltrimethylsilane (14.98mL, 94mmol) in DCM (dry, 70mL) was added BF dropwise over 5 minutes at 0 deg.C₃OEt₂(3.97mL, 31.3 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour, and then by addition of 5% NaHCO₃Aqueous solution (200mL) was quenched. The phases were separated and the aqueous phase was extracted with DCM (50 mL). The combined organic phases were washed with 5% NaHCO₃Aqueous (2x20mL) and brine (20mL), Through Na₂SO₄Dried, filtered and concentrated to dryness in vacuo (40 ℃, ca. 45mbar) to give A6-3 as a pale yellow oil (according to¹H-NMR contains about 16% of the cis isomer; 5.22g, 30.3mmol, 97% yield). The crude product was used in the next step. An analytical method 10; t is t_R＝1.40min。

Step 4.2- ((1R,3S) -3-methyl-2, 3-dihydro-1H-inden-1-yl) acetic acid and dehydroanalog (A6-4)

To a solution of A6-3(5.22g, 30.3mmol) in acetone (130mL) was added sodium periodate (22.68g, 106mmol) and KMnO portionwise over 25 minutes₄(2.87g, 18.18mmol) in H₂Slurry in O (200 mL). The reaction was stirred at 0 ℃ for 20 minutes, then acetone (70mL) was added. After stirring at room temperature for 50 minutes, add in H₂KMnO in O (30mL)₄(2.87g, 18.18mmol) and stirring continued for 80 minutes. Additional acetone (100mL), H was added₂O(100mL)、KMnO₄(2.87g, 18.18mmol) and sodium periodate (6.48g, 30.3mmol), and the reaction was stirred at room temperature for 15 hours 35 minutes. The reaction mixture was filtered, acetone removed in vacuo, and the resulting residue was acidified by addition of 2M aqueous HCl (50 mL). The aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (20mL) and Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: heptane/AcOH (99: 1); eluent B: EtOAc/AcOH (99:1)) to give the desired product A6-4a as a yellow oil along with the dehydroanalog A6-4B (2.579g, 13.56mmol, 45% yield). The product was used in the next step without further purification. An analytical method 15; a6-4a: t _R＝4.15min,[M-H]^-＝189.1；A6-4b:t_R＝3.99min,[M-H]^-＝187.1。

Step 5 (S) -4-benzyl-3- (2- ((1R,3S) -3-methyl-2, 3-dihydro-1H-inden-1-yl) acetyl) oxazolidin-2-one and dehydroanalog (A6-5)

A6-4(A6-4a and A6-4b, 2.579g, 13.56mmol), (S) -4-benzyloxazolidin-2-one (2.402g, 13.56mmol) and DMAP (0.497g, 4.07mmol) were dissolved in DCM (40 mL). The solution was cooled to 0 ℃ under nitrogen atmosphere and DIC (2.9) was added dropwise6mL, 18.98 mmol). The resulting mixture was stirred for 17 hours and then allowed to warm slowly to room temperature. The resulting suspension was filtered and washed with DCM. The filtrate was concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: heptane; eluent B: EtOAc) to give A6-5 as a reddish oil (as a mixture of A6-5a and A6-5B; 3.983g, 11.40mmol, 84% yield). The product was used in the next step without further purification. An analytical method 15; a6-5a: t_R＝6.63min,[M+H]⁺＝350.2；A6-5b:t_R＝6.51min,[M+H]⁺＝348.2。

Step 6.(S) -4-benzyl-3- (2- ((1R,3S) -3-methyl-2, 3-dihydro-1H-inden-1-yl) acetyl) oxazolidin-2-one and cis analog (A6-6)

To A6-5(3.983g, 11.40mmol) in THF (80mL) was added magnesium bromide (2.73g, 14.82mmol) and the resulting mixture was stirred at 55 ℃ for 30 minutes to give a clear solution. After cooling to room temperature, 10% Pd/C (0.364g, 0.342mmol) was added and the resulting suspension was suspended in H ₂Stirring under atmosphere for 26 hours, then filtration through HyFlo. The filtrate was concentrated in vacuo, and the residue was taken up in EtOAc (100mL) and 5% NaHCO₃The aqueous solution (20mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 20mL) and brine (15mL) were washed over Na₂SO₄Drying, filtration, and concentration to dryness in vacuo gave a6-6 (as a mixture containing about 20% of the cis isomer) (3.594g, 10.29mmol, 90% yield) as a yellow oil. The product was used in the next step without purification. An analytical method 15; t is t_R＝6.61；[M+H]⁺＝350.2。

Example 2.5: synthesis of 2- (6, 7-dihydro-5H-cyclopenta [ b ] pyridin-5-yl) acetic acid (A7-3)

Step 1 Ethyl 2- (6, 7-dihydro-5H-cyclopenta [ b ] pyridin-5-ylidene) acetate (A7-1)

To a suspension of NaH (2.072g, 51.8mmol) in THF (60mL) at 0 deg.C was added dropwise over 40 minutesEthyl 2- (diethoxyphosphoryl) -acetate (10.28mL, 51.8 mmol). The resulting mixture was stirred at 0 ℃ for 5 minutes, then 6, 7-dihydro-5H-cyclopenta [ b ] in THF (40mL) was added dropwise over 15 minutes]Pyridin-5-one (4.93g, 37 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 2.5 hours and then quenched by addition of 2M aqueous HCl (25.0mL, 50.0 mmol). THF was removed in vacuo and the resulting residue was taken up in EtOAc (250mL) and 5% NaHCO ₃The aqueous solution (100mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous solution (2 × 40mL) and 5% NaHCO₃Aqueous/brine (1:1) (60 mL). N-butanol (50mL) and brine (50mL) were added and the phases were separated. Passing the organic phase over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave A7-1 as a green black oil (assumed to be 37 mmol). The crude product was used in the next step. An analytical method 10; t is t_R0.79min and 0.84 min; [ M + H ]]⁺＝204.0。

Step 2 Ethyl 2- (6, 7-dihydro-5H-cyclopenta [ b ] pyridin-5-yl) acetate (A7-2)

To A7-1(37mmol) in THF (100mL) was added 10% Pd/C (0.788g, 0.740mmol) in H₂Suspension in O (10mL) and reaction mixture in H₂Stirred under atmosphere for 22 hours and then filtered through HyFlo. The filtrate was concentrated to dryness in vacuo and the crude product was purified by flash chromatography on silica gel (eluent A: heptane/DIEA (98: 2); eluent B: EtOAc/DIEA (98: 2)). The pure fractions were combined and concentrated to dryness in vacuo to give A7-2 as a reddish brown oil (2.805g, 13.67mmol, 37% yield over 2 steps). An analytical method 11; t is t_R＝0.73min；[M+H]⁺＝206.1。

Step 3.2- (6, 7-dihydro-5H-cyclopenta [ b ] pyridin-5-yl) acetic acid (A7-3)

To a7-2(2.805g, 13.67mmol) dissolved in dioxane (30mL) was added 1M NaOH (27.3mL, 27.3mmol) and the resulting mixture was stirred at room temperature for 6 hours to give a clear solution. Removing dioxane under vacuum, adding saturated KH ₂PO₄Aqueous (50mL) and the aqueous phase extracted with EtOAc (17 × 30 mL). The combined organic phases were washed with brine (30mL) and Na₂SO₄Drying, filtering, and vacuum concentratingReduced to dryness to give A7-3-batch 1 as a pale beige solid (1.928g, 10.88mmol, 80% yield). The aqueous phase was concentrated to dryness in vacuo. The resulting residue was suspended in DMA and the suspension was filtered. The residue was washed with DMA and the filtrate was concentrated to dryness in vacuo to give a 7-3-batch 2 as a brown lacquer (425mg, 2.398mmol, 18% yield). The crude product was used in the next step without further purification. Analytical method 11: t is t_R＝0.44min；[M+H]⁺＝178.0。

Example 2.6: synthesis of 2- (2, 3-dihydrobenzofuran-3-yl) acetic acid (A8-3)

Step 1, methyl (E) -4- (2-iodophenoxy) but-2-enoic acid ester (A8-1)

To a mixture of 2-iodophenol (17.60g, 80mmol), K₂CO₃To (11.06g, 80mmol) and KI (13.28g, 80mmol) was added acetone (80mL) and the mixture was cooled to 0 ℃. A solution of (E) -methyl 4-bromobut-2-enoic acid ester (9.56mL, 80mmol) in acetone (40mL) was added dropwise over a period of 15 minutes. After stirring at 0 ℃ for 30 minutes, the cooling bath was removed and stirring was continued for 21.5 hours. The reaction was filtered and the acetone removed in vacuo. The residue was partitioned between EtOAc (150mL) and 1M NaOH (15 mL). The organic phase was washed with 1M NaOH (4X15mL) and brine (15mL) over Na ₂SO₄Drying, filtration and concentration to dryness in vacuo gave A8-1(23.368g, 73.5mmol, 92% yield) as a brown oil, which was used in the next step without purification. An analytical method 10; t is t_R＝1.14min；[M+H]⁺＝319.0。

Step 2 methyl 2- (2, 3-dihydrobenzofuran-3-yl) acetate (A8-2)

To A8-1(19.72g, 62mmol) in THF (210mL) cooled to-100 ℃ under and under an argon atmosphere was added a 1.6M solution of BuLi in hexane (42.6mL, 68.2mmol) in THF (30mL) dropwise over 1 hour 45 min at-100 ℃. The resulting mixture was stirred at-100 ℃ for 1 hour, then saturated NH was added₄Aqueous Cl (40mL) was quenched.The reaction mixture was concentrated in vacuo until most of the THF was removed. The mixture was dissolved in EtOAc (500mL) and 5% KHSO₄The aqueous solution (50mL) was partitioned. Mixing the organic phase with 5% KHSO₄Aqueous (2 × 25mL) and brine (25mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave A8-2 (assumed to be 62mmol) as a yellow oil. The crude product was used in the next step. Another batch of A8-2(10mmol) was synthesized from A8-1(10 mmol). An analytical method 10; t is t_R＝0.91min；[M+H]⁺＝193.0。

Step 3.2- (2, 3-dihydrobenzofuran-3-yl) acetic acid (A8-3)

To A8-2(72mmol) dissolved in dioxane (100mL) was added 1M NaOH (144mL, 144mmol) and the resulting mixture was stirred at room temperature for 70 min. The reaction mixture was partitioned between EtOAc (150mL) and 2M aqueous HCl (80mL) and the aqueous phase was washed with EtOAc (2 × 50 mL). The combined organic phases were washed with 5% KHSO ₄Aqueous (2 × 30mL) and brine (20mL) and washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave A8-3 as a brown solid (assumed to be 72.0 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝[M-H]^-＝177.0。

Example 2.7: synthesis of (S) -2- (2- (tert-butoxy) -2-oxoethyl) -4,4, 4-trifluorobutanoic acid (A14)

Step 1.(S) -4-benzyl-3- (4,4, 4-trifluorobutanoyl) oxazolidin-2-one A14-1

To a solution of (S) -4-benzyloxazolidin-2-one (1.871g, 10.56mmol), DMAP (0.25g, 2.11mmol), and 4,4, 4-trifluorobutyric acid (1.5g, 10.56mmol) in DCM (21mL) was added DCC (2.17g, 6.49mmol) at 0 ℃. The resulting mixture was stirred at room temperature for 16 hours. The resulting milky mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated and the white solid obtained was taken up in EtOAc. The organic phase was washed with saturated NaHCO₃Washing with Na₂SO₄Dried, filtered and concentrated.The crude product was purified by flash column chromatography on silica gel (eluting with 0-50% EtOAc in heptane) to afford the desired compound a14-1(2.7g, 85%) after drying.

Step 2. tert-butyl (S) -3- ((S) -4-benzyl-2-oxooxazolidine-3-carbonyl) -5,5, 5-trifluorovalerate A14-2

To a stirred solution of (S) -4-benzyl-3- (4,4, 4-trifluorobutanoyl) oxazolidin-2-one (2.7g, 8.96mmol) in THF (60L) at-78 ℃ was slowly added 1.0M NaHMDS (10.75mL, 10.75mmol) in THF over a period of 10 minutes and the resulting mixture was stirred at-78 ℃ for 1 hour. Tert-butyl 2-bromoacetate (2.62g, 13.44mmol) was then added dropwise at-78 ℃ and stirred for 2 hours. With saturated NH ₄The reaction mixture was quenched with aqueous Cl and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel (eluting with 0-50% EtOAc in heptane) to afford the desired compound a14-2(2.22g, 60%).

Step 3.(S) -2- (2- (tert-butoxy) -2-oxoethyl) -4,4, 4-trifluorobutanoic acid (A14)

To a stirred solution of tert-butyl (S) -3- ((S) -4-benzyl-2-oxooxazolidine-3-carbonyl) -5,5, 5-trifluorovalerate (2.22g, 5.34mmol) in THF (28.5mL) at 0-5 ℃ was added 30% H₂0₂(2.18mL, 21.37mmol) and stirred at the same temperature for 30 min. Then adding LiOH & H at 0-5 deg.C₂A solution of O (0.512g, 21.37mmol) in water (7.12mL) was added and stirring was continued for 1 hour. The reaction mixture was quenched with saturated aqueous sodium sulfite (1.6L) and saturated aqueous sodium bicarbonate (1.6L). The solvent was removed under reduced pressure, diluted with water, and washed with DCM to remove impurities. The aqueous phase was cooled to 5 ℃ and acidified with 6M HCl (pH about 1.5) and the product extracted with ethyl acetate (3 ×). The combined organic phases were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired compound a14(1.27g, 93%) which was used in the next step without purification.

Example 2.8: synthesis of (R) -2- (4- (tert-butoxy) -2-carboxy-4-oxobutyl) pyridine-1-oxide (A15)

Step 1.(R) -tert-butyl 4- (4-benzyl-2-oxooxazolidin-3-yl) -4-oxobutanoate ester (A15-1)

The title compound a15-1 was prepared following the same procedure described in example 2.7 for intermediate a14-1, starting from (R) -4-benzyloxazolidin-2-one and 4- (tert-butoxy) -4-oxobutanoic acid.

Step 2.(R) -tert-butyl 4- ((R) -4-benzyl-2-oxooxazolidin-3-yl) -4-oxo-3- (pyridin-2-ylmethyl) butanoate (A15-2)

To a round bottom flask containing A15-1(4g, 12.00mmol) in THF (100mL) was added NaHMDS (1M in THF) (14.40mL, 14.40mmol) dropwise at-78 ℃. The resulting mixture was stirred at-78 ℃ for a further 30 minutes and then 2- (bromomethyl) pyridine (2.270g, 13.20mmol) was added portionwise over 40 minutes. The reaction mixture was stirred vigorously at-78 ℃ for 1.5 h, over NH₄Quench with saturated aqueous Cl, and EtOAc and H₂And (4) diluting with oxygen. The separated aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (eluting with 0-100% EtOAc/heptane, the product eluting at about 60% EtOAc) to give a15-2 as a reddish oil (solidified upon storage, 3.68g, 72%).

Step 3.(R) -4- (tert-butoxy) -4-oxo-2- (pyridin-2-ylmethyl) butanoic acid (A15-3)

The title compound a15-3(1.95g, 85%) was prepared according to the procedure described for intermediate a14 in example 2.7, step 3, starting from a15-2(3.68g, 8.67 mmol). This material was used in the next step without purification.

Step 4.(R) -4-tert-butyl 1-methyl 2- (pyridin-2-ylmethyl) succinate (A15-4)

To a solution of A15-3(1.95g, 7.35mmol) in anhydrous MeOH (12mL) and cooled in an ice bath was added TMSCH in hexane₂N₂(11mL, 22.0 mmol). Then the obtained product isThe mixture was warmed to room temperature and stirred for 1 hour. Add another 6mL of TMSCH₂N₂And stirring was continued for another 30 minutes. The reaction mixture was then quenched with acetic acid (8mL, 140mmol) and saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated to give a15-4(1.83g, 89%), which was used in the next step without purification.

Step 5.(R) -2- (4- (tert-butoxy) -2- (methoxycarbonyl) -4-oxobutyl) pyridine 1-oxide (A15-5)

To a solution of A15-4(1.83g, 6.55mmol) in DCM (50mL) was added mCPBA (2.94g, 13.10mmol) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 1 hour, then at room temperature for 1 hour. Addition of NaHCO ₃And the reaction mixture was extracted three times with EtOAc. The organic phases were combined and passed over Na₂SO₄Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 0-15% MeOH/DCM, product eluting at about 15% MeOH) to give the desired product a15-5(1.5g, 78%) as a light brown oil.

Step 6.(R) -2- (4- (tert-butoxy) -2-carboxy-4-oxobutyl) pyridine-1-oxide (A15)

To a solution of A15-5(1.5g, 5.08mmol) in THF (36mL) and ACN (12mL) was added a 1M aqueous LiOH solution (10.16mL, 10.16 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure (in a bath at 25 ℃). The resulting residue was acidified to pH 4 with 4M HCl and extracted three times with DCM. The combined organic phases are passed over Na₂SO₄Drying, filtration and concentration gave a15(1.55g, 98%) as a light thick brown oil, which was used in the next step without purification.

Example 2.9: synthesis of (R) -2- (2- (tert-butoxy) -2-oxoethyl) pentanoic acid (A16)

(R) -2- (2- (tert-butoxy) -2-oxoethyl) pent-4-enoic acid (A16-2)

The title compound a16-2 was prepared according to the procedure described for a15 in example 2.8, steps 2 and 3, starting from intermediate a 15-1.

Step 3.(R) -2- (2- (tert-butoxy) -2-oxoethyl) pentanoic acid (A16)

To a mixture of A16-2(500mg, 2.33mmol) in EtOAc (10mL) was added Pd (OH)₂(100mg, 2.33 mmol). The resulting mixture was washed three times with hydrogen and stirred at room temperature under a hydrogen atmosphere overnight. Then the reaction mixture is passed through

Pad filtration and concentration of the filtrate gave a16(695mg, quantitative yield) as a crude product after drying under high vacuum. This material was used in the next step without purification.

Example 2.10: synthesis of (R) -2- (4- (tert-butoxy) -2-carboxy-4-oxobutyl) -6-methylpyridine 1-oxide (A34)

Step 1.(R) -tert-butyl 4- ((R) -4-benzyl-2-oxooxazolidin-3-yl) -3- ((6-methylpyridin-2-yl) methyl) -4-oxobutanoate (A34-1)

To A15-1(31.19g, 94mmol) in THF (104mL) was added NaHMDS (1M in THF) (112mL, 112mmol) dropwise at-78 ℃. The reaction mixture was stirred at-78 ℃ for a further 30 minutes. 2- (bromomethyl) -6-methylpyridine (19.15g, 103mmol in 15mL THF +20mL DMSO red solution) was then added dropwise over 20 minutes. After addition, the reaction (containing a large amount of solid inside) was stirred at-78 ℃ and then warmed to room temperature overnight to give a dark red solution. The reaction mixture was reacted with saturated NH at room temperature ₄Cl solution quenched with EtOAc/H₂And (4) diluting with oxygen. The aqueous phase was saturated with salt and extracted with EtOAc. All organic phases were combined and passed over Na₂SO₄Dried, filtered and concentrated. The crude product was purified by flash chromatography on a 330g silica gel column (eluting with 0-80% EtOAc/heptane). Purification using a second 330g gold column (with 30-50% EtOAc)Heptane elution) fractions with impurities 26.33g (60mmol, 64.2% yield) of the title product A34-1 were isolated. Analytical method 5, t_R＝1.19,min,[M+H]⁺＝439.5。

Step 2.2- ((R) -2- ((R) -4-benzyl-2-oxooxazolidine-3-carbonyl) -4- (tert-butoxy) -4-oxobutyl) -6-methyl-1 l 4-pyridin-1-olate (A34-2)

To a solution of a34-1(26.33g, 60.0mmol) in DCM (300mL) was added mCPBA (26.9g, 120mmol) as a solid in one portion and the reaction mixture was stirred at room temperature overnight. Once LCMS showed complete consumption of starting material and peaks consistent with complete conversion to the desired product. The reaction mixture was treated with sodium sulfite (7.57g, 60mmol) in water (about 25mL) and then poured into saturated sodium bicarbonate solution. The aqueous phase was extracted twice with DCM. The combined organic phases were again taken up with saturated NaHCO₃The aqueous solution was washed, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography (330g column, adsorbed onto silica, eluting with 0-10% MeOH in DCM) to afford the desired product a34-2(24.39g, 53.7mmol, 89% yield). Analytical method 5, t _R＝1.02,min,[M+H]⁺＝455.4。

Step 3 (R) -2- (4- (tert-butoxy) -2-carboxy-4-oxobutyl) -6-methyl-1 l 4-pyridin-1-olate (A34)

To a round bottom flask containing a34-2(24.39g, 53.7mmol) suspended in THF (286mL) and cooled to 0 ℃, hydrogen peroxide (21.93mL, 215mmol) was added followed by lithium hydroxide (5.14g, 215mmol) in water (72mL), maintaining the internal temperature below 5 ℃, and the resulting mixture was stirred at 0 ℃. After 2 hours LCMS showed complete consumption of the starting material (oxazolidinone hydrolyzed only). The reaction mixture was quenched by addition of saturated aqueous sodium thiosulfate solution and then stirred overnight. The mixture was concentrated to remove THF, partitioned with DCM, and transferred to a separatory funnel. The phases were separated and the aqueous phase was extracted with DCM (2 ×). These organic phases are discarded. The aqueous phase was acidified to pH 1 using 1M HCl and then partitioned with EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc (2 ×). The combined (EtOAc) organic phases were washed with brine, thenDrying over sodium sulfate, filtration and concentration gave 10.95g (37.1mmol, 69.1% yield) of the desired substance A34. Analytical method 5, t_R＝0.43,min,[M+H]⁺＝296.3。

Unless otherwise indicated, the following intermediates in table 2A were prepared according to the procedure described above for the succinate building block, using the appropriate starting materials:

Table 2A:

example 3: synthesis of building Block B-diamines

Example 3.1: synthesis of tert-butyl (R) - (1- (4-chlorophenyl) -3- (methylamino) propan-2-yl) (methyl) carbamate (B1)

Step 1.(R) -2- ((tert-butoxycarbonyl) (methyl) amino) -3- (4-chlorophenyl) propanoic acid (B1-1)

To N-Boc-D-Phe (4-Cl) -OH (2.30g, 7.67mmol) dissolved in THF (25mL) and cooled to 0 deg.C was added NaH (0.921g, 23.02mmol) and the resulting suspension was stirred at 0 deg.C for 40 min. Methyl iodide (3.84mL, 61.4mmol) was then pushed in and stirring continued for 16 h 20 min. The reaction mixture was warmed to room temperature and then purified by addition of H₂O (2mL) quenched and then in EtOAc (70mL) and 5% KHSO₄The aqueous solution (40mL) was partitioned. Mixing the organic phase with 5% KHSO₄Aqueous (2 × 15mL) and brine (15mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave B1-1 as a beige oil (assumed to be 7.67 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.05min；[M-H]^-＝312.1。

Step 2. tert-butyl (R) - (3- (4-chlorophenyl) -1- (methylamino) -1-oxoprop-2-yl) (methyl) carbamate (B1-2)

To B1-1(3.83mmol), TBTU (1.599g, 4.98mmol) and HOBT (0.587g, 3.83mmol) in DMF (25mL) was added DIEA (1.539mL, 8.81mmol) and the resulting solution was stirred at room temperature for 20 min. Methylamine in EtOH (33%, 0.954mL, 7.66mmol) was added and the reaction mixture was stirred at room temperature for 105 minutes and concentrated in vacuo. The resulting residue was taken up in EtOAc (70mL) and 5% NaHCO ₃The aqueous solution (20mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 15mL) and brine (15mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave B1-2 as a pale yellow solid (assumed to be 3.83 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.06min；[M+H]⁺＝327.1。

Step 3. tert-butyl (R) - (1- (4-chlorophenyl) -3- (methylamino) propan-2-yl) (methyl) carbamate (B1)

Step 3-1: b1-2(3.83mmol) was dissolved in THF (20mL) and BH was added₃DMS (1.091mL, 11.49 mmol). The reaction was stirred at 50 ℃ for 18 hours.

Step 3-2: the reaction mixture from step 3-1 was quenched by addition of meoh (ml). The resulting solution was stirred at 50 ℃ for 75 minutes and then concentrated to dryness in vacuo.

Step 3-3: to the residue from step 3-2 dissolved in MeOH (25mL) was added H₂10% Pd/C (0.122g, 0.115mmol) in O (2mL), and the resulting suspension was stirred at 50 ℃ for 18.5, then filtered through HyFlo. The filtrate was concentrated to dryness in vacuo to afford B1 as a pale yellow oil (1.183g, 3.78mmol, 99% yield over 3 steps). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝0.80min；[M+H]⁺＝313.2。

The following Building Blocks (BB) in table 3 were synthesized according to the method described for building block B1 in example 3.1.

Table 3: building Block B-diamines

Example 3.2: synthesis of tert-butyl (R) - (1- (4-chlorophenyl) -3- (1-methylcyclopropane-1-carboxamide) propan-2-yl) (methyl) carbamate (B5-1)

To 1-methylcyclopropanecarboxylic acid (0.400g, 4.00mmol) and TBTU (1.284g, 4.00mmol) in DMF (5mL) was added DIEA (1.40 mL; 8.00mmol) and the resulting solution was stirred at room temperature for 5 min. B3 in DMF (5mL) was then added and stirring continued at room temperature for 14.5 h. Addition of H₂O (1mL), and the resulting mixture was dissolved in EtOAc (75mL) and 5% NaHCO₃The aqueous solution (15mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 15mL) and brine (10mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave B5-1 as a light brown oil (assumed to be 4.00 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.17min；[M+H]⁺＝381.3。

Example 3.3: synthesis of tert-butyl 3-amino-3- (4-chlorobenzyl) piperidine-1-carboxylate (B8) and tert-butyl (R) -3-amino-3- (4-chlorobenzyl) piperidine-1-carboxylate (B2)

Step 1. tert-butyl 3-amino-3- (4-chlorobenzyl) piperidine-1-carboxylate (B8)

Step 1-1: to 1- (tert-butoxycarbonyl) -3- (4-chlorobenzyl) piperidine-3-carboxylic acid (6.905g, 19.51mmol) dissolved in toluene (100mL) and DIEA (5.11mL, 29.3mmol) was added diphenylphosphoryl azide (5.48mL, 25.4mmol), and the resulting mixture was stirred at room temperature for 2.5 hours, then at 100 ℃ for 4 hours. The reaction mixture was purified in EtOAc (300mL) and 5% NaHCO ₃The aqueous solution (60mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 60mL) and brine (50mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo.

Step 1-2: to the residue from step 1-1 dissolved in dioxane (200mL) was added 1M NaOH (195mL, 195 mmol). The resulting mixture was stirred at room temperature for 1 hour, then concentrated to dryness in vacuo. The resulting residue was taken up in EtOAc (250mL) and 5% Na₂CO₃The aqueous solution (20mL) was partitioned and the aqueous phase was extracted with EtOAc (70 mL). The combined organic phases were washed with 5% Na₂CO₃Aqueous solution (40mL) and brine (40mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave racemate B8 (assumed to be 19.5mmol) as a yellow oil, which was used in the next step without further purification. An analytical method 10; t is t_R＝0.80min；[M+H]⁺＝325.2。

Step 2. tert-butyl (R) -3-amino-3- (4-chlorobenzyl) piperidine-1-carboxylate (B2)

Racemate B8(19.5mmol) was isolated by preparative SFC (instrument: Thar 200 preparative SFC) using the following conditions: column: chiralPak AD,300 × 50mm I.D.,10 μm; eluent A: CO 2₂(ii) a Eluent B: EtOH (0.1% NH)₄OH); gradient: b45 percent; flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ℃; cycle time: about 9 min; compound dissolved in about 130mL MeOH; and (3) injection: 10 mL/injection. B2 (slower eluting isomer) was obtained as a colourless oil (2.66 g; 7.78 mmol; 40%). Partial crystallization occurs upon storage, allowing confirmation of the structure by X-ray crystallography. An analytical method 10; t is t _R＝0.77min；[M+H]⁺＝325.3。

Example 3.3: synthesis of (R) -3- (4-chlorobenzyl) piperidin-3-amine hydrochloride (B7)

To B2(2.09g, 6.43mmol) dissolved in dioxane (10mL) was added dioxane (50mL) and H₂4M HCl in O (5mL) and the resulting solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness in vacuo to afford B7(1.818g, 6.11mmol, 95% yield) as a pale beige foam. The crude product was used in the next step without purification. An analytical method 10; t is t_R＝0.40min；[M+H]⁺＝225.1。

Example 4: synthesis of building blocks AB

Example 4.1: synthesis of (S) -4- (((R) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) (methyl) amino) -3- (4-chlorophenyl) -propyl) (methyl) amino) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid (AB1)

Step 1. tert-butyl (S) -4- (((R) -2- ((tert-butoxycarbonyl) (methyl) amino) -3- (4-chlorophenyl) propyl) (methyl) -amino) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoate (AB1-1)

To A3(417mg, 1.436mmol) dissolved in DCM (20mL) was added HATU (601mg, 1.580mmol) and DIEA (0.301mL, 1.723mmol), and the resulting mixture was stirred at room temperature for 30 min. A solution of B1(642mg, 1.867mmol) in DCM (10mL) and DIEA (0.752mL, 4.31mmol) was then added and the reaction mixture was stirred at room temperature for 4 h. Additional B1(99mg, 0.287mmol) was added and stirring continued at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resulting residue was taken up in EtOAc (60mL) and 5% NaHCO ₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous solution (2 × 10mL), 5% KHSO₄Aqueous solution (10mL) and brine (10mL) were washed with Na₂SO₄Dried, filtered and concentrated to dryness in vacuo to afford AB1-1 as a yellow oil (assumed 1.436 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.55min；[M+H]⁺＝585.4。

Step 2.(S) -4- (((R) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) (methyl) amino) -3- (4-chlorophenyl) propyl) - (methyl) amino) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid (AB1)

Step 2-1: AB1-1(1.435mmol) was dissolved in 95% aqueous TFA/DCM (1:1) (20mL) and the resulting solution was stirred at room temperature for 90 min, then concentrated to dryness in vacuo.

Step 2-2: to the residue from step 2-1 dissolved in dioxane (16mL) was added 0.5M Na₂CO₃Aqueous solution (8.61mL, 4.31mmol) and a solution of Fmoc-OSu (0.484g, 1.435mmol) in dioxane (10 mL). The resulting mixture was stirred at room temperature for 18.5 hours, then quenched by the addition of 2M aqueous HCl (10 mL). Dioxane was removed in vacuo, EtOAc (75mL) was added, and the phases were separated. Mixing the organic phase with 5% KHSO₄Aqueous (2 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: heptane/AcOH (99: 1); eluent B: EtOAc/AcOH (99: 1)). The pure fractions were combined and concentrated to dryness in vacuo. The residue was taken up in EtOAc (70mL) and 5% NaHCO ₃The aqueous solution (5mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous solution (3 × 5mL), 5% KHSO₄Aqueous solution (10mL) and brine (10mL) were washed with Na₂SO₄Dry, filter, and concentrate to dryness in vacuo to afford AB1 as a colorless lacquer (661mg, 1.015mmol, 71% over 2 steps). An analytical method 10; t is t_R＝1.41min；[M+H]⁺＝651.2。

The following Building Blocks (BB) in table 4 were synthesized according to the procedure described for building blocks AB1 in example 4.1 and AB14 in example 4.3 from the monomers in tables 1 and 3.

Table 4: construction of the Block AB

Example 4.2: synthesis of tert-butyl (R) -4- (((R) -2- ((tert-butoxycarbonyl) (methyl) amino) -3- (4-chlorophenyl) propyl) - (methyl) amino) -3- (dimethylamino) -4-oxobutanoate (AB13-2)

Step 1. tert-butyl (R) -3- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4- (((R) -2- ((tert-butoxycarbonyl) - (methyl) amino) -3- (4-chlorophenyl) propyl) (methyl) amino) -4-oxobutanoate (AB13-1)

To A13(362mg, 0.88mmol) and TBTU (311mg, 0.968mmol) in DCM/DMF (2:1) (15mL) was added DIEA (0.231mL, 1.320mmol) and the resulting solution was stirred at room temperature for 40 min. A solution of B1(391mg, 1.250mmol) in DMF (2.5mL) was added and stirring continued at room temperature for 150 min. The reaction mixture was concentrated in vacuo, then in EtOAc (60mL) and 5% NaHCO ₃The aqueous solution (20mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered and concentrated to dryness in vacuo to afford AB13-1 as a pale yellow oil (ca. 0.88 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.54min；[M+H]⁺＝706.5。

Step 2. tert-butyl (R) -4- (((R) -2- ((tert-butoxycarbonyl) (methyl) amino) -3- (4-chlorophenyl) propyl) (methyl) -amino) -3- (dimethylamino) -4-oxobutanoate (AB13-2)

Step 2-1: to AB13-1(0.88mmol) in THF (20mL) was added PS-thiophenol (852mg, 1.320mmol) and DBU (0.027mL, 0.176mmol), and the resulting suspension was stirred at room temperature for 2 h 40 min. The solution was filtered off and the resin was carefully washed with DCM. The combined filtrates were concentrated to dryness in vacuo.

Step 2-2: to the residue from step 2-1 dissolved in THF (20mL) was added 37% aqueous HCHO (0.262mL, 3.52mmol) and the resulting solution was stirred at room temperature for 20 minutes. Then NaBH (OAc) is added₃(0.746g, 3.52mmol) and the reaction mixture was stirred at room temperature for 15 h 40 min. Additional 37% aqueous HCHO (0.262mL, 3.52mmol) was added and stirring continued at room temperature for 1 hour 20 minutes. Addition of additional NaBH (OAc) ₃(0.746g, 3.52mmol) and stirring was continued for 4 hours. MeOH (2mL) was added and stirring was continued for 90 min. AcOH (0.101mL, 1.760mmol) was added and the mixture was stirred for 3 hours. Additional 37% HCHO in water (0.262mL, 3.52mmol) and NaBH (OAc) were added₃(0.746g, 3.52mmol) and stirring continued at room temperature for 13.5 h. The reaction mixture was concentrated in vacuo, and the resulting residue was taken up in EtOAc (50mL) and 5% Na₂CO₃The aqueous solution (15mL) was partitioned. The organic phase was washed with 5% Na₂CO₃Aqueous (2 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: heptane/DIEA (98: 2); eluent B: EtOAc/DIEA (98: 2)). The pure fractions were combined and concentrated to dryness in vacuo to give AB13-2 as a colorless oil (335mg, 0.654mmol, 74% in 2 steps). An analytical method 10; t is t_R＝1.09min；[M+H]⁺＝512.0。

Example 4.3: synthesis of (R) -4- ((R) -3- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxo-3- (pyridin-3-ylmethyl) butanoic acid (AB14)

Step 1. tert-butyl (R) -4- ((R) -3- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxo-3- (pyridin-3-ylmethyl) butanoate (AB14-1)

Step 1-1: to a solution of A2(491mg, 1.500mmol) and TBTU (482mg, 1.500mmol) in DMA (10mL) was added DIEA (0.341mL, 1.950 mmol). The resulting mixture was stirred at room temperature for 5 minutes, then a solution of B7(446mg, 1.50mmol) in DMA (10mL) and DIEA (1.048mL, 6.00mmol) was added. The reaction mixture was stirred at room temperature for 3.25 hours, then the DMA was removed in vacuo. The resulting residue was taken up in EtOAc (70mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃(3X10mL) and brine (10mL) over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo to give a light brown oil.

Step 1-2: to the residue from step 1-1 dissolved in DCM (10mL) was added DIEA (0.524mL, 3.00mmol), and a solution of Fmoc-Cl (388mg, 1.500mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The resulting residue was taken up in EtOAc (60mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: heptane/DIEA (98: 2); eluent B: EtOAc/DIEA (98: 2)). The pure fractions were combined and concentrated to dryness in vacuo. The residue was dissolved in DCM and the solution was concentrated to dryness in vacuo to give AB14-1 as a white foam (775mg, 1.116mmol, 74% yield). An analytical method 10; t is t _R＝1.47min；[M+H]⁺＝694.5。

Step 2.(R) -4- ((R) -3- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxo-3- (pyridin-3-ylmethyl) butanoic acid (AB14)

To a solution of AB14-1(774mg, 1.115mmol) and 2, 6-lutidine (1.298mL, 11.15mmol) in DCM (15mL) was added TM dropwise at 0 deg.CSOTf (1.007mL, 5.57mmol) and the reaction mixture was stirred at 0 ℃ for 2.5 h. Add EtOAc (60mL) and 5% NaHCO₃Aqueous solution (5mL) and the phases were separated. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 5mL) and brine (10 mL). The combined aqueous phases were extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with brine (10mL) and combined with the first organic phase. The combined organic phases are passed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The residue was dissolved in DCM and the solution was concentrated to dryness in vacuo to give AB14 as a beige foam (about 1.115 mmol). The crude product was used in the next step without further purification. An analytical method 10; t is t_R＝1.20min；[M+H]⁺＝638.3。

Example 4.4: synthesis of methyl (S) -4- ((R) -3-amino-3- (4-chlorobenzyl) piperidin-1-yl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoate (AB17)

Step 1. tert-butyl (R) -4- ((R) -3-amino-3- (4-chlorobenzyl) piperidin-1-yl) -4-oxo-3- (pyridin-3-ylmethyl) butanoate (AB17-1)

To a solution of A3(93mg, 320. mu. mol) and TBTU (103mg, 320. mu. mol) in DMA (4mL) was added DIEA (0.073mL, 416. mu. mol). The resulting solution was stirred at room temperature for 15 minutes, then a solution of B7(117mg, 320. mu. mol) in DMA (3mL) and DIEA (0.291mL, 1664. mu. mol) was added. The reaction mixture was stirred at room temperature for 16.5 h, then in EtOAc (50mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃(2X10mL) and brine (10mL) over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave AB17-1 (assumed to be 0.32 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.12min；[M+H]⁺＝497.2。

Step 2 methyl (S) -4- ((R) -3-amino-3- (4-chlorobenzyl) piperidin-1-yl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoate (AB17)

To AB17-1(0.30mmol) dissolved in MeOH (10mL) was added SOCl₂(0.219mL, 3.00mmol), and the resulting mixture was stirred at room temperature for 3.5 hours. Addition of additional SOCl₂(0.438mL, 6.00mmol) and stirring was continued at room temperature for 24 h. More SOCl was added₂(0.438mL, 6.00mmol) and the resulting mixture was stirred at room temperature for 16.5 and then concentrated to dryness in vacuo. The residue obtained was taken up in EtOAc (50mL) and 5% NaHCO ₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo to afford AB17(123mg, 0.270mmol, 90% over 2 steps) as a yellow oil. The product was used in the next step without purification. An analytical method 10; t is t_R＝0.96min；[M+H]⁺＝455.2。

Example 5: construction of Block C-alpha-amino acids

Table 5 shows the α -amino acids used as building blocks C.

Table 5: construction of Block C-alpha-amino acids

Example 6: construction of Block D-alpha-amino acids

Example 6.1: synthesis of (S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -6-morpholinohexanoic acid trifluoroacetate (D2)

Step 1-1: to Boc-Lys-OtBu HCl (339mg, 1.00mmol) and K₂CO₃To (415mg, 3.00mmol) was added DMA (8mL) and 1-bromo-2- (2-bromoethoxy) ethane (0.126mL, 1.000 mmol). The resulting suspension was stirred at 70 ℃ for 18 h, then in EtOAc (60mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous solution (2x10mL) and saltWashed with water (10mL) and Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was used in the next step without purification.

Step 1-2: the residue from step 1-1 was dissolved in 95% aqueous TFA (10mL) and the resulting solution was stirred at room temperature for 1 hour and then concentrated to dryness in vacuo. The crude product was used in the next step without purification.

Step 1-3: to a solution in dioxane (5mL) and H₂To the residue from step 1-2 in O (2mL) was added 0.5M Na₂CO₃Aqueous solution (6.00mL, 3.00mmol) and a solution of Fmoc-OSu (304mg, 0.900mmol) in dioxane (2 mL). The reaction mixture was stirred at room temperature for 90 minutes and then quenched by the addition of 2M aqueous HCl (3 mL). Dioxane was removed in vacuo and the crude residue was taken up in EtOAc (50mL) and H₂Partition between O (10 mL). The organic phase was washed with brine (10 mL). The combined aqueous phases were extracted with EtOAc (20mL) and the resulting organic phase was washed with brine (5 mL). The combined organic phases are passed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give D2(264.5mg, 0.479mmol, 48% yield) as a white solid. An analytical method 10; t is t_R＝0.71min；[M+H]⁺＝439.3。

Table 6 shows the α -amino acids used as building blocks D.

Table 6: construction of Block D-alpha-amino acids

Example 6.2: synthesis of (S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4-fluorobutyric acid (D5)

Step 1.3- (tert-butyl) 4-methyl (4S) -1,2, 3-oxathiazinane-3, 4-dicarboxylate 2-oxide (D5-1)

To a solution of imidazole (173.4g, 2.55mol) and triethylamine (132.0mL, 939mmol) in DCM (3L) at 4 deg.C was added SOCl dropwise over 1 hour ₂(65 mL). The suspension was stirred at 4 ℃ for 25 minutes and a solution of methyl (tert-butoxycarbonyl) -L-homoserine ester (110.65g, 90% content, 427.0mmol) in DCM (0.5L) was added over 30 minutes. The reaction mixture was stirred at 4 ℃ for 2 hours 20 minutes, then by addition of H₂O (1.2L) quench. The phases were separated and the aqueous phase was extracted with DCM (0.5L). The combined organic phases are washed with H₂O (1L) and brine (1L) over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography. D5-1(78.14g, 279.8mmol, 66% yield) was obtained as a yellow oil.

Step 2.3- (tert-butyl) 4-methyl (4S) -1,2, 3-oxathiazinane-3, 4-dicarboxylate 2-oxide (D5-2)

To a solution of D5-1(97.3g, 348.4mmol) in ACN (1.8L) and EtOAc (180mL) at 0 deg.C was added RuCl₃ H₂O (4.19g, 20.2mmol) and subsequent addition of NaIO over 15 minutes₄(149.0g, 696.7mmol) in H₂Turbid solution in O (800 mL). The reaction mixture was stirred at 0 ℃ for 85 min, then Et was added₂O (1400 mL). The resulting suspension was filtered and the phases were separated. With Et₂The aqueous phase was extracted with O (2x800 mL). The combined organic phases are washed with NaHCO₃The solution (1000mL) was washed with brine, Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave D5-2 as a white solid (92.75g, 282.7mmol, NMR purity 90%, 81% yield). The crude product was used in the next step without purification.

Step 3 methyl (S) -2- ((tert-butoxycarbonyl) amino) -4-fluorobutyrate (D5-3)

To D5-2(92.75g, 90% purity, 282.7mmol) in ACN (1L) at room temperature was slowly added 1M tetrabutyl in THFAmmonium fluoride (466.5 mL; 466.5mmol) and the reaction mixture was stirred at 60 ℃ for 2 h. The solvent was evaporated in vacuo and the resulting oil was mixed with 4M aqueous HCl (800mL) and heated to 60 ℃ for 90 minutes with stirring. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was co-evaporated to dryness with toluene to give a viscous yellow oil. The crude intermediate was dissolved in MeOH (1200mL) and SOCl was added at 5 deg.C₂(102.6mL, 1.41mol), and the resulting mixture was stirred at reflux for 22 hours. After complete consumption of the starting material, the solvent was removed in vacuo and the crude product was co-evaporated to dryness with toluene.

Dissolved in 1M NaHCO at 5 deg.C₃Boc was added to the obtained oil in aqueous solution and dioxane (200mL)₂A solution of O (124.1g, 568.6mmol) in dioxane (100mL) and the resulting mixture was warmed to room temperature and stirred for 21 hours. Addition of H₂O (500mL) and Et₂O (500mL), and the phases were separated. With Et₂The aqueous phase was extracted with O (2 × 500 mL). The combined organic phases are washed with H ₂O (500mL) and brine (300mL) over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography. D5-3(55.0g, 233.8mmol, 83% yield) was obtained as a yellow oil.

Step 4.(S) -2-amino-4-fluorobutyric acid (D5-4)

D5-3(55.0g, 233.8mmol) was dissolved in 4M HCl (1000mL) and the reaction mixture was stirred at 95 ℃ for 17 h, then concentrated in vacuo. Further drying was achieved by co-evaporation with toluene. D5-4(33.94g, 194mmol, 90% purity, 83% yield) was obtained as a yellow solid.

Step 5 (S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4-fluorobutyric acid (D5)

To a solution of 0.5M NaHCO₃To D5-4(33.9g, 194mmol) in an aqueous solution (1L, 500mmol) was added ACN/THF (4: 1). The resulting mixture was cooled to 0 ℃ and a solution of Fmoc-OSu (75.35g, 223.4mmol) in ACN/THF (4:1) (500mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 23.5 hours. Ice (1000mL) was added and the reaction mixture was carefully acidified to a pH of about 2-3 by the addition of concentrated HCl (25 mL).Addition of Et₂O (2L), and the phases were separated. With Et₂The aqueous phase was extracted with O (600 mL). The combined organic phases are washed with H₂O (600mL) and brine, over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography. The pure fractions were combined and concentrated to dryness in vacuo. The resulting residue was suspended in toluene (150mL) and the suspension was concentrated to dryness in vacuo. This step was repeated twice. D5 was obtained as an off-white solid (17.5g, 50.7mmol, 26% yield). An analytical method 10; t is t _R＝0.96min；[M+H]⁺＝344.1。¹H NMR(600MHz,DMSO-d₆)δ12.75(s,1H),7.88(d,J＝7.5Hz,2H),7.71(t,J＝7.2Hz,2H),7.40(t,J＝7.4Hz,2H),7.32(t,J＝7.4Hz,2H),4.55(dt,J＝9.7,5.0Hz,0.5H),4.48(dt,J＝9.7,4.8Hz,1H),4.40(td,J＝8.9,4.4Hz,0.5H),4.30(d,J＝7.1Hz,2H),4.22(t,J＝7.0Hz,1H),4.06(td,J＝9.6,4.4Hz,1H),2.14(dtt,J＝19.0,8.7,4.4Hz,1H),1.92(dtd,J＝31.2,10.2,5.1Hz,1H)。

Example 7: construction of Block E-aldehydes

Example 7.1: synthesis of 4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) -benzaldehyde (E2)

Step 1.5-bromo-1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazole (E2-1)

To a solution of 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (1.890g, 10.0mmol) in DCM (70mL) was added pyrrolidine (1.643mL, 20.0 mmol). After stirring at room temperature for 25 minutes, NaBH (OAc) was added₃(8.48g, 40.0 mmol). The reaction mixture was stirred at room temperature for 105 minutes and then concentrated to dryness in vacuo. The resulting residue was partitioned between EtOAc (250mL) and 1M aqueous NaOH (50 mL). The organic phase was washed with 1M NaOH (2X40mL) and brine (20mL) over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave E2-1 as a yellow solid (assumed to be 10.0 mmol). The crude product was used in the next step without purification. Analytical method 11；t_R＝0.66min；[M+H]⁺＝244.1。

Step 2.4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenol (E2-2)

To E2-1(10.0mmol), (4-hydroxyphenyl) boronic acid (2.76g, 20.0mmol) and [1,1' -bis (di-tert-butylphosphino) -ferrocene]To palladium (II) dichloride (0.978g, 1.50mmol) was added dioxane (30mL) and 1M Na₂CO₃Aqueous solution (30mL) and the resulting mixture in N ₂Stirred at 100 ℃ for 4 hours under an atmosphere. Additional (4-hydroxyphenyl) boronic acid (1.379g, 10.0mmol) was added and stirring continued at 100 ℃ for 135 minutes. Additional (4-hydroxyphenyl) boronic acid (1.379g, 10.0mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene were then added]Palladium (II) dichloride (0.244g, 0.375mmol) and motif stirring at 100 ℃ for 18.75 h. Add EtOAc (250mL) and H₂O (50mL), and the mixture was filtered through Hyflo. The phases were separated and the organic phase was purified with 5% NaHCO₃Aqueous (3 × 40mL) and brine (40mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: EtOAc/MeOH/DIEA (95:5: 2); eluent B: EtOAc/MeOH/DIEA (85:15:2)) to give E2-2 as a brown solid (2.28g, 8.86mmol, 89% over 2 steps). An analytical method 11; t is t_R＝0.76min；[M+H]⁺＝258.1。

Step 3.4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzaldehyde (E2)

To E2-2(1.029g, 4mmol) and 4-chloro-2-fluorobenzaldehyde (0.824g, 5.20mmol) dissolved in NMP (20mL) was added K₂CO₃(1.437g, 10.40 mmol). The resulting mixture was stirred at 80 ℃ for 18H, then in EtOAc (125mL) and H₂Partition between O (20 mL). The organic phase was washed with 5% NaHCO ₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: EtOAc/DIEA (98: 2); eluent B: EtOAc/MeOH/DIEA (90:10:2)) to give E2(1.25g, 3.16mmol, 79% yield) as a brown oil. An analytical method 10; t is t_R＝0.79min；[M+H]⁺＝396.2。

E9 was synthesized following the procedure described for E2 in example 7.1, starting from E9-4, (4-hydroxyphenyl) boronic acid and 4-chloro-2-fluorobenzaldehyde as starting materials.

Example 7.2: 4-chloro-2- (4- (1-methyl-2- (morpholinomethyl) -1H-imidazol-5-yl) phenoxy) benzaldehyde (E3)

Step 1.5- (4-hydroxyphenyl) -1-methyl-1H-imidazole-2-carbaldehyde (E3-1)

5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (1.890g, 10mmol), (4-hydroxyphenyl) boronic acid (2.76g, 20.00mmol), and Pd (PPh)₃)₄(0.578g, 0.500mmol) in DMF (40mL) and 1M Na₂CO₃Mixture of aqueous solution (30mL, 30.0mmol) in N₂Stirred at 90 ℃ for 5 hours under an atmosphere. The mixture was filtered through HyFlo and the filtrate was taken up in EtOAc (100mL) and H₂Partition between O (50 mL). The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (20mL) and Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave E3-1 as an olive solid (assumed to be 10 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t _R＝0.60min；[M+H]⁺＝203.1。

Step 2.4- (1-methyl-2- (morpholinomethyl) -1H-imidazol-5-yl) phenol (E3-2)

To E3-1(2.5mmol) was added DCM (10mL) and morpholine (0.431mL, 5.00 mmol). The resulting mixture was stirred at room temperature for 140 minutes, then NaBH (OAc) was added₃(1060mg, 5.00 mmol). The reaction mixture was stirred at room temperature for 2.5 h, then in EtOAc (70mL) and 5% NaHCO₃The aqueous solution (15mL) was partitioned. The aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (5mL) and Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave E3-2 as a pale olive solid (677mg, 2.477mmol, 99% yield over 2 steps). The crude product is purifiedCan be used for the next step. An analytical method 10; t is t_R＝0.42min；[M+H]⁺＝274.2。

Step 3.4-chloro-2- (4- (1-methyl-2- (morpholinomethyl) -1H-imidazol-5-yl) phenoxy) benzaldehyde (E3)

To 4-chloro-2-fluorobenzaldehyde (550mg, 3.47mmol) and K₂CO₃(890mg, 6.44mmol) to a solution of E3-2(677mg, 2.477mmol) in NMP (10mL) was added. The suspension was stirred at 80 ℃ for 21 hours. The reaction mixture was washed with EtOAc (60mL) and H₂Partition between O (15 mL). The organic phase was washed with 5% NaHCO₃Aqueous (2 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: EtOAc/DIEA (98: 2); eluent B: EtOAc/MeOH/DIEA (85:15: 2)). Pure fractions were combined and concentrated to dryness in vacuo to give E3 as a beige solid (579mg, 1.406mmol, 57% yield). An analytical method 10; t is t _R＝0.81min；[M+H]⁺＝412.1。

The following Building Blocks (BB) in table 7 were synthesized according to the procedures described for building block E2 in example 7.1, building block E3 in example 7.2, building block E12 in example 7.7, building block E17 in example 7.10, and building block E23 in example 7.14.

Table 7: construction of Block F-aldehydes

Example 7.3: synthesis of 3, 5-difluoro-4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenol (E8-3)

Step 1.3, 5-difluoro-4- (1-methyl-1H-imidazol-5-yl) phenol (E8-1)

Step 1-1: to 2, 6-difluoro-4-hydroxybenzaldehyde (949mg, 6.00mmol) dissolved in DCM (20mL) was added 2M methylamine (9.00mL, 18.00mmol) in methanol, followed by MgSO₄(4333mg, 36.0 mmol). The resulting suspension was stirred at room temperature for 13.5 hours and then filtered. The obtained residue was washed with DCM (about 40mL) and the filtrate was concentrated to dryness in vacuo to give an orange brown solid which was used in the next step without purification.

Step 1-2: to TOSMIC (1523mg, 7.80mmol) was added a solution of the residue of step 1-1 in MeOH (15mL) and DIEA (3.14mL, 18.00 mmol). The resulting mixture was stirred at 70 ℃ for 3 hours and then concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: EtOAc/MeOH/DIEA (95:5: 2); eluent B: EtOAc/MeOH/DIEA (90:10:2)) to give E8-1 as a beige solid (960mg, 4.57mmol, 76% yield). An analytical method 11; t is t _R＝0.71min；[M+H]⁺＝211.1。

Step 2.5- (2, 6-difluoro-4-hydroxyphenyl) -1-methyl-1H-imidazole-2-carbaldehyde (E8-2)

To E8-1(0.420g, 2.00mmol) dissolved in THF (5mL) and TTPA (5mL) (tris (N, N-tetramethylene) phosphoric acid triamide) and cooled to-30 deg.C was added N-BuLi (1.6M in hexane) (7.50 mmol) dropwisemL, 12.00 mmol). The reaction mixture was stirred at-25 ℃ to-35 ℃ for 65 minutes (some gel was formed after addition of n-BuLi). Additional TTPA (1.0mL) and n-BuLi (1.6M in hexanes) (1.25mL, 2.00mmol) were added and stirring continued at-25 ℃ for 5 minutes. DMF (1.55mL, 20.0mmol) was then added dropwise and the resulting mixture was stirred for 1 hour and then warmed to-10 ℃. The reaction mixture was quenched by the addition of AcOH (0.916mL, 16.0mmol) and washed with EtOAc (50mL) and 5% NaHCO₃(15 mL). The organic phase was washed with 5% NaHCO₃Aqueous (2 × 10mL) and brine (10mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave E8-2 as a yellow oil (ca. 2.0 mmol). The crude product was used in the next step without purification. An analytical method 11; t is t_R＝1.10min；[M+H]⁺＝239.1。

Step 3.3, 5-difluoro-4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenol (E8-3)

E8-2(2.0mmol) was dissolved in DCM (20mL) and pyrrolidine (0.331mL, 4.00 mmol). The resulting solution was stirred at room temperature for 5 minutes and NaBH (OAc) was added ₃(0.848g, 4.00 mmol). The reaction mixture was stirred at room temperature for 45 min, then partitioned between EtOAc (40mL) and 1M aqueous HCl (10 mL). The organic phase was extracted with 1M aqueous HCl (3 × 10 mL). The combined aqueous phases were basified to pH 8-9 by addition of 4M aqueous NaOH and then washed with EtOAc (3x40 mL). The combined organic phases were washed with brine (20mL) and Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave E8-3 as a yellow oil (ca. 2.0 mmol). The crude product was used in the next step without purification. An analytical method 11; t is t_R＝0.84min；[M+H]⁺＝294.2。

Example 7.4: synthesis of (R) -1- (5-bromo-1-methyl-1H-imidazol-2-yl) -N, N-dimethylethyl-1-amine (E9-4)

Step 1.(R, E) -N- ((5-bromo-1-methyl-1H-imidazol-2-yl) methylene) -2-methylpropane-2-sulfinamide (E9-1)

To 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (3g, 15.87mmol) in anhydrous DCM (40mL) was added (R) -2-methylpropane-2-sulfinamide (2.116g, 17.46mmol) and anhydrous copper sulfate (5.07g, 31.7 mmol). The resulting mixture was stirred at room temperature overnight and then passed

The pad was filtered and washed with DCM. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (eluting with 0 → 100% EtOAc in heptane) to give E9-1(4g, 13.69mmol, 86% yield) as a white solid. Analytical method 5; t is t _R＝0.83min；[M+H]⁺＝294.2。

Step 2.(R) -N- ((R) -1- (5-bromo-1-methyl-1H-imidazol-2-yl) ethyl) -2-methylpropane-2-sulfinamide (E9-2)

To a solution of E9-1(2.7g, 9.24mmol) in anhydrous DCM (50mL) at-50 deg.C was added 3M MeMgBr in diethyl ether (7.08mL, 21.25mmol) by syringe and the resulting mixture was stirred at-50 deg.C for 1 hour, and then with saturated NH₄And (4) quenching by using a Cl aqueous solution. After warming to room temperature, the reaction mixture was quenched with saturated NaHCO₃Aqueous solution (50mL) was diluted and extracted with DCM (2 × 60 mL). The combined organic phases are passed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo to afford a white solid. The product was recrystallized from EtOAc/heptane to give E9-2 as a white powder (2.03g, 6.59mmol, 71% yield). Analytical method 5; t is t_R＝0.68min；[M+H]⁺＝310.1。

Step 3 (R) -1- (5-bromo-1-methyl-1H-imidazol-2-yl) ethylamine hydrochloride (E9-3)

To a suspension of E9-2(2.02g, 6.55mmol) in anhydrous MeOH (10mL) was added 4M HCl in dioxane (6.55mL, 26.2 mmol). The resulting mixture became clear and was stirred at room temperature for 1 hour. Diethyl ether (100mL) was added, resulting in the formation of a precipitate. The precipitate was collected by filtration to give E9-3 as a white powder (about 6.55 mmol). The crude material was used in the next step without purification. Analytical method 5; t is t _R＝0.51min；[M+H]⁺＝203.9。

Step 4.(R) -1- (5-bromo-1-methyl-1H-imidazol-2-yl) -N, N-dimethylethylamine (E9-4)

To E9-3(6.55mmol) were added anhydrous DCM (50mL), paraformaldehyde (1.967g, 65.5mmol), NaBH (OAc)₃(3.47g, 16.38mmol) and AcOH (5 mL). The resulting mixture was stirred at room temperature for two days. Addition of additional NaBH (OAc)₃(1600mg, 7.55mmol) and paraformaldehyde (600mg, 20.0 mmol). The reaction mixture was stirred overnight and then over 2N Na₂CO₃Aqueous solution (100mL) was quenched and extracted with DCM (2 × 100 mL). The combined organic phases are passed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave E9-4 as a yellow oil (1.46g, 3.14mmol, 48% over 2 steps). The crude material was used in the next step without purification. Analytical method 5; t is t_R＝0.66min；[M+H]⁺＝233.9。

Example 7.5: synthesis of tert-butyl 3- (5- (4-hydroxyphenyl) -1-methyl-1H-imidazol-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (E10-4)

Step 1.5- (4- (benzyloxy) phenyl) -1-methyl-1H-imidazole (E10-1)

To (4- (benzyloxy) phenyl) boronic acid (2.281g, 10.00mmol), 5-bromo-1-methyl-1H-imidazole (1.610g, 10.00mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]To palladium (II) dichloride (0.326g, 0.500mmol) was added dioxane (25mL) and 1M Na₂CO₃Aqueous solution (25mL, 25.00 mmol). The resulting mixture is stirred under N ₂Stir under atmosphere at 100 ℃ for 2.5H, and then in EtOAc (200mL) and H₂Partition between O (20 mL). The organic phase was washed with 5% NaHCO₃Aqueous solution (3 × 25mL) and brine, washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: EtOAc/DIEA (98: 2); eluent B: EtOAc/MeOH/DIEA (90:10:2)) to give E10-1(1.173g, 4.44mmol, 44% yield). An analytical method 10; t is t_R＝0.75min；[M+H]⁺＝265.2。

Step 2.5- (4- (benzyloxy) phenyl) -2-iodo-1-methyl-1H-imidazole (E10-2)

Dissolve in THF (50mL) over 10 min at-50 deg.C, cool to-50 deg.C and in N₂To E10-1(538mg, 2.035mmol) under an atmosphere was added 1.6M n-BuLi in hexane (1.781mL, 2.85mmol) dropwise. After stirring at-50 ℃ for 20 minutes, additional 1.6M n-BuLi in hexane (0.509mL, 0.814mmol) was added dropwise over 5 minutes. The brown suspension turned into a red solution. After stirring for 10 min at-50 ℃, N-iodosuccinimide (641mg, 2.85mmol) in THF (5mL) was added dropwise over 10 min. The reaction mixture was stirred at-50 ℃ for 1 hour, and then by addition of H₂O (10mL) quench. THF was removed in vacuo and the resulting residue was taken up in EtOAc (80mL) and 5% NaHCO ₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 5mL) washes. The combined aqueous phases were washed with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (15mL) and Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: heptane/DIEA (98: 2); eluent B: EtOAc/DIEA (98:2)) to give E10-2 as a beige solid (372mg, 0.953mmol, 47% yield). An analytical method 10; t is t_R＝1.12min；[M+H]⁺＝391.0。

Step 3.4- (2-iodo-1-methyl-1H-imidazol-5-yl) phenol (E10-3)

E10-2(405.3mg, 1.039mmol) was dissolved in 95% aqueous TFA/thioanisole (95:5) solution (20mL) and the resulting mixture was stirred at room temperature for 43 hours, then concentrated to dryness in vacuo. The residue obtained was taken up in EtOAc (70mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude residue was purified by flash chromatography on silica gel (eluent A: heptane/DIEA (98: 2); eluent B1: EtOAc/DIEA; eluent B2: EtOAc/MeOH/DIEA (90:10:2)) to give E10-3(165mg, 0.55mmol, 53% yield). An analytical method 10; t is t _R＝0.55min；[M-H]^-＝299.0。

Step 4. tert-butyl 3- (5- (4-hydroxyphenyl) -1-methyl-1H-imidazol-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (E10-4)

To E10-3(450mg, 1.50 mmol; from several batches), tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (531mg, 1.800mmol) and [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (48.9mg, 0.075mmol) to which dioxane (8mL) and 1M Na were added₂CO₃(4.50mL, 4.50 mmol). The resulting mixture is stirred under N₂Stir at 90 ℃ for 90 min under atmosphere, then in EtOAc (50mL) and H₂Partition between O (10 mL). The organic phase was washed with 5% NaHCO₃(2X10mL) and brine (10mL) over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave E10-4 as a brown solid (ca. 1.50 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝0.72min；[M+H]⁺＝342.2。

Example 7.6: synthesis of 4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) -6- (2,2, 2-trifluoroethoxy) benzaldehyde (E11)

Step 1.4-chloro-2-fluoro-6- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzaldehyde (E11-1)

To 4-chloro-2, 6-difluorobenzaldehyde (88mg, 0.50mmol), E2-2(129mg, 0.500mmol) and K ₂CO₃To (207mg, 1.500mmol) was added NMP (2.5mL), and the resulting suspension was left to stand at room temperature for 16 hours with stirring and then at 60 ℃ for 7.5 hours. The solution containing E11-1 was used for the next step.

Step 2.4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) -6- (2,2, 2-trifluoro-ethoxy) -benzaldehyde (E11)

2,2, 2-trifluoroethanol (0.044mL, 0.600mmol) was added to the solution containing E11-1 and the resulting mixture was addedStirring was carried out at 80 ℃ for 22 hours. Additional 2,2, 2-trifluoroethanol (0.044mL, 0.600mmol) was added and stirring continued at 80 ℃ for 21 h. The reaction mixture was washed with EtOAc (50mL) and H₂Partition between O (10 mL). The organic phase was washed with 5% NaHCO₃Aqueous (3 × 10mL) and brine, washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: EtOAc/DIEA (98: 2); eluent B: EtOAc/MeOH/DIEA (90:10:2)) to give E11(165mg, 0.334mmol, 67% over 2 steps). An analytical method 10; t is t_R＝0.87min；[M+H]⁺＝494.2。

Example 7.7: synthesis of 2- (4- (2- (azetidin-1-ylmethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzaldehyde (E12)

Step 1.4- (2- (azetidin-1-ylmethyl) -1-methyl-1H-imidazol-5-yl) phenol (E12-1)

To a solution of E3-1(500mg, 2.47mmol) in THF (25mL) was added azetidine (0.33mL, 4.95mmol) and acetic acid (0.42mL, 7.42 mmol). The resulting mixture was stirred at room temperature for 1 hour, then NaBH (OAc) was added in one portion₃(1.15g, 5.44 mmol). The reaction mixture was stirred at rt overnight, quenched with MeOH and concentrated. The crude product was taken up in 20% IPA in DCM and washed once with saturated sodium bicarbonate. The aqueous phase was then extracted again with 20% IPA in DCM. The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give E12-1 as a foam (602mg, quantitative yield) after drying. This material was used in the next step without purification. Analysis method 5: t is t_R＝0.77min；MS[M+H]⁺＝244.2。

Step 2.2- (4- (2- (azetidin-1-ylmethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzaldehyde (E12)

E12-1(171mg, 0.70mmol) in N, N-dimethylformamide (3.5mL) and potassium carbonate (486mg, 3.51mol) were placed in a round bottom flask. Mixing the obtained mixtureAfter stirring at room temperature for 30 minutes, 4-chloro-2-fluorobenzaldehyde (123mg, 3.51mmol) was added. The resulting solution was stirred at 90 ℃ for 2.5 h using an oil bath, cooled to room temperature, diluted with water, and extracted with EtOAc (3 ×). The combined organic phases were washed with half-saturated NaHCO ₃The solution was washed with brine, and then Na₂SO₄Dried, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (eluting with dichloromethane/methanol) to give E12(150mg, 56%). Analysis method 5: t is t_R＝0.99min[M+H]⁺＝382.2。

Example 7.8: synthesis of 4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzaldehyde (E14)

Step 1.5- (5- (benzyloxy) pyridin-2-yl) -1-methyl-1H-imidazole-2-carbaldehyde (E14-1)

To a mixture of 5-bromo-2- (dimethoxymethyl) -1-methyl-1H-imidazole (6.2g, 26.4mmol) in THF (80mL) at-78 ℃ under nitrogen was added i-PrMgCl LiCl complex (1.3M in THF, 24.35mL, 31.6mmol) and the resulting mixture was stirred at-78 ℃ for 15 minutes (cloudy mixture). Then Bu is added₃SnCl (8.15mL, 29.0mmol) and stirring at-78 deg.C for an additional 15 minutes (clear solution) and at room temperature for 1 hour (clear solution). 5- (benzyloxy) -2-bromopyridine (8.36g, 31.6mmol) and Pd (PPh) were added₃)₄(3.05g, 2.64mmol) and the resulting mixture was diluted with 50mL dioxane, flushed three times with nitrogen and then refluxed at 105 ℃ for 2-3 days.

After cooling to room temperature, the reaction mixture was passed through

And (5) filtering. The filtrate was quenched with 0.5N HCl (50mL) at 0 deg.C and the organic solvent was removed under reduced pressure. EtOAc was added to extract the product. The combined organic phases were washed with water, brine and Na ₂SO₄Drying, filtering andand (5) concentrating. The crude product was purified by flash column chromatography on silica gel (300g) eluting with 10% MeOH/DCM. The fractions containing the desired compound were combined and concentrated under reduced pressure. To the residue were added 50mL of THF, 2.5mL of water, and 25mL of 6N HCl. The resulting mixture was stirred at room temperature overnight, heated at 80 ℃ for 6 hours, cooled, and then quenched with NaHCO₃The saturated aqueous solution was neutralized and extracted with EtOAc (300 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by flash column chromatography (300g silica gel column, eluting with 50% -90% EtOAc/heptane) to afford E14-1(5.8g, 95%).¹H NMR(400MHz,DMSO-d₆)δ9.75(s,1H),8.50(d,J＝2.8Hz,1H),7.84(d,J＝8.8Hz,1H),7.72(s,1H),7.62(dd,J＝8.8,3.0Hz,1H),7.53-7.47(m,2H),7.45-7.39(m,2H),7.39-7.33(m,1H),5.27(s,2H),4.20(s,3H)。

Step 2.1- (5- (5- (benzyloxy) pyridin-2-yl) -1-methyl-1H-imidazol-2-yl) -N, N-dimethylmethylamine (E14-2)

A mixture of E14-1(4.35g, 14.83mmol) and dimethylamine (2M in THF, 44.5mL, 89mmol) in DCM (200mL) was stirred at room temperature for 1 h. Then add NaBH (OAc) in portions₃(9.43g, 44.5mmol) and the resulting mixture stirred at room temperature for 1 hour and then quenched with 0.5mL AcOH and 1mL water. The phases are separated and the organic phase is treated with saturated NaHCO₃The solution was washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (330g silica gel column, eluting with about 20% to 50% MeOH in DCM) to afford E14-2(5g, 99%). ¹H NMR(400MHz,DMSO-d₆)δ8.39(d,J＝2.9Hz,1H),7.63(d,J＝8.8Hz,1H),7.54-7.46(m,3H),7.46-7.38(m,2H),7.39-7.30(m,1H),7.21(s,1H),5.22(s,2H),3.87(s,3H),3.48(s,2H),2.16(s,6H)。

Step 3.6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-ol (E14-3)

To a solution of 1- (5- (5- (benzyloxy) pyridin-2-yl) -1-methyl-1H-imidazol-2-yl) -N, N-dimethylmethylamine (E14-2, 4.4g, 13.65mmol) in MeOH (60mL) and THF (20mL) was added Pd (OH)₂(10% on carbon, 0.575g, 4.09mmol) and the resulting mixture was flushed three times with hydrogen and hydrogen using a balloonStirred under a gas atmosphere for 4 hours. After complete consumption of the starting material was observed by LCMS, the reaction mixture was flushed with nitrogen and passed

Filtering, and mixing

The pad was washed with MeOH. The filtrate was concentrated and dried under high vacuum to give E14-3(2.0g, about 80% pure) and 1.53g (about 85% pure) of 14-3, which was used in the next step without purification;¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),8.17(d,J＝2.9Hz,1H),7.49(d,J＝8.2Hz,1H),7.21(dd,J＝8.7,2.9Hz,1H),7.12(s,1H),3.85(s,3H),3.48(s,2H),2.16(s,6H)。

step 4.4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzaldehyde (E14)

The mixture was charged with E14-3(1g, 4.31mmol), 4-chloro-2-fluorobenzaldehyde (0.887g, 5.60mmol) and Cs₂CO₃A flask of (1.824g, 5.60mmol), DMF (5mL) was flushed three times with nitrogen and held at 60 ℃ for 16 hours. Upon observation of complete consumption of starting material and formation of product (LCMS showed product at t)_R0.92 min), the reaction mixture was filtered and concentrated to provide a crude oil. The crude product was passed through a reverse phase flash column (with 5% -80% water/ACN (with 0.1% NH) ₄OH) elution). Fractions containing the desired product were combined and concentrated in vacuo. Addition of NaHCO₃The solution was saturated (50mL) and the resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic phases are washed with NaHCO₃Washed with water, brine, and Na over saturated aqueous solution (2 × 50mL)₂SO₄Drying, filtration and concentration under reduced pressure gave product E14(1.04g, 2.80mmol, 65%).¹H NMR(400MHz,DMSO-d₆)δ10.36(s,1H),8.55(d,J＝2.9Hz,1H),7.89(d,J＝8.4Hz,1H),7.80(d,J＝8.2Hz,1H),7.70(dd,J＝8.8,2.9Hz,1H),7.42(dd,J＝8.3,1.9Hz,1H),7.38(s,1H),7.16(d,J＝1.9Hz,1H),3.94(s,3H),3.51(s,2H),2.17(s,6H)。

Example 7.9: synthesis of 2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-ethylbenzaldehyde (E15)

To a mixture of E14-3(456mg, 1.972mmol) and 4-ethyl-2-fluorobenzaldehyde (300mg, 1.972mmol) in anhydrous DMF (5mL) was added K₂CO₃(2180mg, 15.77 mmol). The resulting mixture was heated and stirred at 90 ℃ under nitrogen atmosphere>For 5 hours or more to complete the reaction. The reaction mixture was cooled to room temperature, diluted with 15mL of water, and extracted with 2 × 15mL of EtOAc. The combined organic phases were washed with 3x10mL water and 2x15mL aqueous 1.0N HCl. The aqueous phases were combined and combined with 1M K₂CO₃The solution was basified to give a cloudy mixture. The aqueous phase was then extracted with 2 × 20mL EtOAc, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (330g column, eluting with 10% MeOH in DCM) to give E15(300mg, 41.9%) as a yellow oil.

Example 7.10: synthesis of tert-butyl ((5- (4- (5-chloro-3-fluoro-2-formylphenoxy) phenyl) -1-methyl-1H-imidazol-2-yl) methyl) carbamate (E17)

4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenol (E17-1) was prepared starting from the corresponding aldehyde and tert-butylamine according to the procedure described in example 7.7, step 1 for the construction of block E12.

Step 1.2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzaldehyde (E17-2)

The title compound E17-2 was prepared according to the procedure described for the construction of block E12 in example 7.7, step 2, starting from 4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenol (E17-1) and 1.2 equivalents of 4-chloro-2, 6-difluorobenzaldehyde.

Step 2 tert-butyl ((5- (4- (5-chloro-3-fluoro-2-formylphenoxy) phenyl) -1-methyl-1H-imidazol-2-yl) methyl) carbamate (E17)

To a solution of E17-2(1.27g, 3.05mmol) in DCM (20mL) was added Boc in one portion₂O (1g, 4.58 mmol). The resulting mixture was stirred at room temperature overnight, then another 0.5 equivalents of Boc was added₂O to ensure complete conversion of the starting material to the product. The reaction mixture was then quenched with water and extracted twice with DCM. The organic phase was dried over sodium sulfate, filtered and concentrated to give E17(1.5g, 95%) as a pale yellow foam. The crude product was of sufficient purity to be used in the next step without purification.

Example 7.11: synthesis of 4-chloro-2- (4- (4- ((dimethylamino) methyl) -5-methyl-1H-imidazol-1-yl) phenoxy) benzaldehyde (E19)

Step 1.1- (1- (4- (benzyloxy) phenyl) -5-methyl-1H-imidazol-4-yl) -N, N-dimethylmethylamine E19-2

The title compound E19-2 was prepared according to the procedure described in example 7.7, step 2 for the construction of block E12, starting from E19-1 and using THF as solvent.

Step 2.4- (4- ((dimethylamino) methyl) -5-methyl-1H-imidazol-1-yl) phenol B11-3

To a round bottom flask containing E19-2(1.45g, 4.51mmol) and THF (12mL) and MeOH (12mL) was added Pearlman's catalyst (Pd (OH)₂290mg, 2.07mmol), and the resulting mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was flushed with nitrogen gas through

The pad was filtered and concentrated to give E19-3(1.02g, 98%) after drying. The product was of sufficient purity to be used in the next step without purification.

Step 3.4-chloro-2- (4- (4- ((dimethylamino) methyl) -5-methyl-1H-imidazol-1-yl) phenoxy) benzaldehyde (E19)

The title compound E19 was prepared starting from E19-3 according to the procedure described in example 7.7, step 2 for the construction of block E12.

Example 7.12: synthesis of 1- (4- (benzyloxy) phenyl) -5-methyl-1H-imidazole-4-carbaldehyde (E19-1)

Step 1, ethyl 5-methyl-1- (4-nitrophenyl) -1H-imidazole-4-carboxylate (E19-A)

To a round bottom flask containing 1-fluoro-4-nitrobenzene (100g, 0.71mol) and ethyl 4-methyl-1H-imidazole-5-carboxylate (101g, 0.71mol) in DMF (800mL) was added potassium carbonate (392g, 2.84mmol) and the resulting mixture was heated to 100 ℃ and stirred for 4 hours. The reaction mixture was then cooled to room temperature and poured into an ice bath to provide a slurry. The mixture was filtered and the filter cake was dried under high vacuum to give E19-a as a pale yellow solid (170g, 87%).¹H NMR(400MHz,DMSO-d₆):δ8.42(d,J＝6.8Hz,2H),8.01(s,1H),7.83(d,J＝6.8Hz,2H),4.27(q,J＝7.2Hz,2H),2.47(s,3H),1.30(t,J＝7.2Hz,2H)。

Step 2 ethyl 1- (4-aminophenyl) -5-methyl-1H-imidazole-4-carboxylate (E19-B)

To the cooled mixture of B19-A (85g, 0.31mol) in ethanol (700mL) and in an ice bath was added acetic acid (200mL), followed by iron powder (69g, 1.24 mol). The ice bath was then removed and the resulting mixture was heated to 100 ℃ for 1 hour and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and partitioned between DCM and water. Passing the organic phase over Na₂SO₄Drying, filtration and concentration under reduced pressure gave E19-B (55g, 73%) as a gummy material, which was used in the next step without purification.¹H NMR(400MHz,CDCl₃):δ7.56(s,1H),7.02(d,J＝8.0Hz,2H),6.75(d,J＝8.4Hz,2H),6.20(bs,2H),4.38(q,J＝7.2Hz,2H),2.41(s,3H),1.41(t,J＝7.2Hz,2H)。

Step 3 ethyl 1- (4-hydroxyphenyl) -5-methyl-1H-imidazole-4-carboxylate (E19-C)

To the cooled mixture of E19-B (25g, 0.10mol) in water (2L) and in an ice bath was added sulfuric acid (35%, 100 mL). The resulting mixture was stirred for 10 minutes, then NaNO was added₂(14g, 0.23 mol). The reaction mixture was stirred at 0 ℃ for a further 10 minutes and urea (6.13g, 0.10mol) was added. The mixture was then warmed to room temperature and Cu (NO) was added₃)₂(370g, 1.53mol, 0.5M) aqueous solution, followed by addition of solid Cu₂O (7.3g, 0.05 mol). The resulting mixture was stirred at room temperature for 3 hours, then quenched with aqueous ammonia and extracted repeatedly with 10% methanol in DCM. The combined organic phases are passed over Na₂SO₄Drying, filtration, and concentration under reduced pressure gave E19-C as an off-white solid (16g, 64%). The crude compound was used in the next step without further purification.

Step 4. Ethyl 1- (4- (benzyloxy) phenyl) -5-methyl-1H-imidazole-4-carboxylate (E19-D)

To an ice-cold suspension of NaH (2.85g, 71.4mmol) in DMF (75mL) was added a solution of E19-C (16g, 65mmol) in DMF (75mL) and the resulting mixture was allowed to warm to room temperature and then stirred for 1h before benzyl bromide (13.3g, 78mmol) was added. The reaction mixture was stirred at room temperature>After 2 h, quench with ice-cold water and extract twice with EtOAc. Passing the organic phase over Na ₂SO₄Dried, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluting with 40% EtOAc in ether) to give E19-D as a light yellow solid (8g, 37%).¹H NMR(400MHz,CDCl₃):δ7.50(s,1H),7.48-7.36(m,5H),7.18(d,J＝8.8Hz,2H),7.08(d,J＝8.8Hz,2H),5.12(s,2H),4.39(q,J＝7.2Hz,2H),2.43(s,3H),1.42(t,J＝7.2Hz,2H)。

Step 5 (1- (4- (benzyloxy) phenyl) -5-methyl-1H-imidazol-4-yl) methanol (E19-E)

To a cooled solution of B19-D (10g, 30mmol) in THF (150mL) and in an ice bath was added DIBAL-H (1M in toluene, 98mL, 98mmol) and the resulting mixture was stirred in the ice bath for 2H, then quenched with water (21mL) and 15% aqueous NaOH (6 mL). The reaction mixture was then gradually warmed to room temperature, stirred for 15 minutes, filtered, and the filtrate was concentratedThe solution was concentrated under reduced pressure to give E19-E (8g, 91%) as an off-white solid after drying.¹H NMR(400MHz,DMSO-d₆):δ7.59(s,1H),7.48(d,J＝6.8Hz,2H),7.41(t,J＝7.2Hz,2H),7.36-7.30(m,3H),7.14(dd,J₁＝2.0Hz,J₂＝6.8Hz,2H),5.17(s,2H),4.70(t,J＝5.6Hz,1H),4.34(d,J＝5.6Hz,1H),2.09(s,3H)。

Step 6.1- (4- (benzyloxy) phenyl) -5-methyl-1H-imidazole-4-carbaldehyde (E19-1)

To oxalyl chloride (4.7mL, 54mmol) in CH₂Cl₂DMSO (7.7mL, 108mmol) was added dropwise to the solution in (80mL) cooled to-78 ℃. The resulting mixture was stirred at-78 ℃ for 10 minutes, then E19-E (8g, 27mmol) in CH was added dropwise₂Cl₂(60 mL). The reaction mixture was stirred at-78 ℃ for 10 minutes and Et was added dropwise₃N (23mL, 162 mmol). The reaction mixture was allowed to warm to room temperature and stirred >For 3 hours, dilute with water and extract twice with DCM. The combined organic phases are passed over Na₂SO₄Dried, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified using a Grace preparative HPLC system eluting with 0-100% petroleum ether/EtOAc to afford E19-1 as an off-white solid after concentration of the pure fractions under reduced pressure (4g, 50%).¹H NMR(400MHz,CDCl₃):δ9.88(s,1H),7.92(s,1H),7.49-7.35(m,7H),7.19(d,J＝6.8Hz,2H),5.19(s,2H),2.39(s,3H)。

Example 7.13: synthesis of 4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6- (2,2, 2-trifluoroethoxy) benzaldehyde (E22)

To a mixture of E13(1.64g, 3.81mmol) and potassium carbonate (2.63g, 19.03mmol) in NMP (10mL) was added 2,2, 2-trifluoroethanol (1.25mL, 17.29mmol) in one portion. Will react in N₂The mixture was heated to 80 ℃ under atmosphere overnight, cooled to room temperature and diluted with EtOAc (150 mL). The organic phase is treated with H₂O (1x100mL, 1x75mL), saturated NaHCO₃Aqueous solution (50mL) and brine (50 m)L) washing over Na₂SO₄Dried, filtered, and concentrated in vacuo to afford a dark orange oil. The crude oil was purified by flash column (eluting with 10% MeOH: 90% DCM (with 1% TEA)) to give E22 as a tan oil after concentration of the pure fractions (1.02g, 1.96mmol, 51.6%).

Example 7.14: synthesis of 4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) -3-fluorophenoxy) benzaldehyde (E23)

Step 1.5- (4- (benzyloxy) -2-fluorophenyl) -1-methyl-1H-imidazole-2-carbaldehyde (E23-1)

The title compound E23-1 was prepared according to the procedure described for the construction of block E12 in example 7.7, step 1, starting from 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde and (4- (benzyloxy) -2-fluorophenyl) boronic acid.

Steps 2 to 4.4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) -3-fluorophenoxy) benzaldehyde (E23)

The title compound was prepared starting from E23-1 according to the procedure described for the construction of block B14 in example 7.8, steps 2 to 4.

Example 7.15: synthesis of 4-chloro-2- (4- (5- ((dimethylamino) methyl) -4-methyl-4H-1, 2, 4-triazol-3-yl) phenoxy) benzaldehyde (E26)

Step 1.2- (4- (benzyloxy) benzoyl) -N-methylhydrazinethiocarboxamide (E26-1)

To a microwave vial containing 4- (benzyloxy) benzoyl hydrazide (556mg, 2.30mmol) was added THF and methyl isothiocyanate (185mg, 2.52 mmol). The resulting mixture was gently heated with a heat gun to provide a clear liquid, then heated to 130 ℃ in a microwave for 10 minutes. The resulting white slurry was cooled to room temperature, filtered, and washed with EtOAc to give E26-1 as a white solid after drying (656mg, 91%). The product was used in the next step without purification.

Step 2.5- (4- (benzyloxy) phenyl) -4-methyl-2, 4-dihydro-3H-1, 2, 4-triazole-3-thione (E26-2)

To a microwave vial containing E26-1(656mg, 2.08mmol) was added a solution of NaOH (2M, 9.26mL, 18.51 mmol). The resulting mixture was capped, heated to 150 ℃ in a microwave for 5 minutes, cooled to room temperature, neutralized with AcOH, and extracted three times with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to give E26-2 as crude product (600mg, 97%). The product was used in the next step without purification.

Step 3.3- (4- (benzyloxy) phenyl) -4-methyl-4H-1, 2, 4-triazole (E26-3)

To the cooled mixture of E26-2(600mg, 2.02mmol) in DCM (4mL) and in an ice bath was added dropwise a solution of hydrogen peroxide (35%, 0.393mL, 4.48mmol) and acetic acid (3mL, 52.5 mmol). The resulting mixture was then warmed to room temperature and stirred overnight. The reaction mixture was cooled using an ice bath and NaOH (2M) was added dropwise until pH was about 10, resulting in a biphasic layer. The separated aqueous phase was extracted twice with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (eluting with 0-10% DCM/MeOH) to afford E26-3(433mg, 81%) after concentration of the pure fractions.

Step 4.5- (4- (benzyloxy) phenyl) -4-methyl-4H-1, 2, 4-triazole-3-carbaldehyde (E26-4)

Step 4-1: to a mixture of E26-3(433mg, 1.63mmol) in o-xylene (2mL) was added paraformaldehyde (250mg, 8.32mmol) at room temperature. The reaction mixture was heated to 125 ℃ for 3 hours. The resulting slurry was cooled to room temperature, taken up in DCM, and passed through

The pad was filtered and the filtrate was concentrated. The crude product was triturated with MeOH, filtered, and dried to give the alcohol intermediate as a white solid (447mg, 93%).

Step 4-2 to a mixture of the alcohol (447mg, 1.51mmol) from step 4-1 in THF (6mL) at room temperatureManganese dioxide (1.49g, 171mmol) was added. The resulting mixture was stirred at room temperature overnight and then passed

The pad was filtered and the filtrate was concentrated to dryness. The crude product was purified by flash column chromatography (eluting with 0-60% DCM/ACN) and the pure fractions were concentrated under reduced pressure to give E26-4(98mg, 20%).

Steps 5 to 7.4-chloro-2- (4- (5- ((dimethylamino) methyl) -4-methyl-4H-1, 2, 4-triazol-3-yl) phenoxy) benzaldehyde (E26)

The title compound E26 was prepared from E26-4 according to the procedure described in example 7.8, steps 2 to 4 for the construction of block B14.

Example 7.16: synthesis of tert-butyl 3- (5- (4- (5-chloro-2-formylphenoxy) phenyl) -1-methyl-1H-imidazol-2-yl) azetidine-1-carboxylate (E27)

Step 1.4- (1-methyl-1H-imidazol-5-yl) phenol (E27-1)

The title compound E27-1 was prepared according to the procedure described for the construction of block E12 in example 7.7, step 1, starting from (4-hydroxyphenyl) boronic acid and 5-bromo-1-methyl-1H-imidazole.

Step 2.5- (4- ((tert-butyldiphenylsilyl) oxy) phenyl) -1-methyl-1H-imidazole (E27-2)

To a solution of E27-1(3g, 17.22mmol) in DMF (34.4mL) was added DMAP (0.526g, 4.31mmol) and Huning base (DIPEA, 9.02mL, 51.7mmol) followed by tert-butyldiphenylsilyl chloride (5.31mL, 20.67 mmol). The resulting mixture was stirred overnight, then diluted with EtOAc and half saturated sodium bicarbonate solution, and the aqueous phase was extracted with EtOAc (2 ×). The combined organic phases were washed with half-saturated aqueous sodium bicarbonate solution (2 ×), water (2 ×) and brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting the impurities first with 100% acetone and then with 0-10% MeOH in DCM/MeOH to give E27-2(2g, 4.85mmol, 28.1%) after concentration of the pure fractions under reduced pressure.

Step 3.5- (4- ((tert-butyldiphenylsilyl) oxy) phenyl) -2-iodo-1-methyl-1H-imidazole (E27-3)

To a solution of E27-2(1.85g, 4.48mmol) in THF (44.8mL) at 0 deg.C was added n-butyllithium (2.152mL, 5.38mmol) dropwise to give a dark mixture. After stirring at 0 ℃ for 30 min, the reaction mixture was cooled to-78 ℃ and iodine (1.423g, 5.60mmol) in THF (5mL) was added dropwise. The resulting mixture was stirred at-78 ℃ for 1 hour, quenched by addition of water, and concentrated to remove most of the THF. EtOAc was added. The organic phase was washed with aqueous sodium thiosulfate and brine, dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography on silica gel (eluting with 0-100% EtOAc/heptane) afforded E27-3(1.98g, 3.68mmol, 82%)

Step 4. tert-butyl 3- (5- (4- ((tert-butyldiphenylsilyl) oxy) phenyl) -1-methyl-1H-imidazol-2-yl) azetidine-1-carboxylate E27-4

To a suspension of zinc powder (1.821g, 27.9mmol) in DMA (8mL) were added TMSCl (0.237mL, 1.857mmol) and 1, 2-dibromoethane (0.160mL, 1.857mmol), and the resulting mixture was stirred for 15 minutes. Tert-butyl 3-iodoazetidine-1-carboxylate (2.58mL, 14.86mmol) was then added dropwise as a solution in DMA (4mL) and the reaction mixture was heated to 35 ℃ for 1 hour with stirring. To E27-3(1g, 1.857mmol), Pd (dppf) under nitrogen atmosphere₂To a mixture of (0.152g, 0.186mmol) and copper (I) iodide (0.071g, 0.371mmol) in DMA (8mL) was added a zincate mixture and the resulting mixture was stirred at 85 ℃ for 2 hours and then at room temperature overnight. The reaction mixture was washed with EtOAc and H₂And (4) distributing among the O. The organic phase is treated with H₂O (x3) was washed and the combined aqueous phases were extracted with EtOAc. The combined organic phases were washed with brine and then dried (Na)₂SO₄) Filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (eluting with DCM/MeOH, 0-10%) to give the desired product containing some impurities. The material was purified again by flash column chromatography (silica gel column; heptane/EtOAc 0-100%) and concentrated Pure fractions gave E27-4(220mg, 0.387mmol, 20.9%).

Step 5. tert-butyl 3- (5- (4- (5-chloro-2-formylphenoxy) phenyl) -1-methyl-1H-imidazol-2-yl) azetidine-1-carboxylate (E27)

To a mixture of E27-4(137mg, 0.241mmol) and 4-chloro-2-fluorobenzaldehyde (42mg, 0.265mmol) in DMF (2.4mL) was added cesium fluoride (55mg, 0.362mmol) and potassium carbonate (50mg, 0.362mmol) at room temperature. The resulting mixture was then heated to 90 ℃ overnight, cooled to room temperature, and then filtered. The filtrate was taken up in EtOAc and washed with a saturated solution of sodium bicarbonate (× 2) and brine, dried over sodium sulfate, filtered and concentrated. The crude product was combined with another batch (total 0.417mmol) and purified by flash column chromatography on silica gel (eluting with 0-60% DCM/ACN) to give E27(110mg, 56%) after concentration of the pure fractions under reduced pressure.

Example 7.17: synthesis of 2, 4-difluoro-6- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzaldehyde (E29)

The title compound E29 was prepared according to the procedure described for the construction of block E12 in example 7.7, step 2, starting from the corresponding phenol and 2 equivalents of 2,4, 6-trifluorobenzaldehyde. After work-up and purification, E29 was isolated as a 1:1 mixture containing regioisomers of the desired product E29 and 2, 6-difluoro-4- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzaldehyde.

Example 7.18: synthesis of 4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-ethyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzaldehyde (E31)

Step 1. (5-bromo-1-ethyl-1H-imidazol-2-yl) methanol (E31-1)

To (1-ethyl-1H-imidazol-2-yl) methanol (4g, 31.7mmol) in THF (85mL)NBS (5.44g, 30.6mmol) was added portionwise over 30 minutes to a mixture of (cooled to-20 deg.C) (dry ice in 30% MeOH in water), and the resulting mixture was stirred at-20 deg.C and slowly warmed to 0 to 5 deg.C over 4.5 hours the cooling bath was removed the reaction mixture was stirred at room temperature overnight and quenched with 60mL of saturated aqueous sodium bicarbonate solution at room temperature and stirring continued for 30 minutes the mixture was concentrated to remove most of the THF, then extracted with EtOAc (x3)₃The aqueous solution was washed, dried over sodium sulfate, filtered and concentrated to give a crude solid which was triturated with EtOAc, filtered and washed with a small amount of EtOAc to give E31-1 as a white solid after drying. Additional product was obtained from the filtrate. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluting with 0-100% DCM/ACN) to give another crop of product (2.5 g product in total, 39%).

Step 2.5-bromo-1-ethyl-1H-imidazole-2-carbaldehyde (E31-2)

To a mixture of E31-1(2.18g, 10.63mmol) in DCM (42mL) cooled in an ice bath was added dess-martin periodinane (9.02g, 21.26mmol) over 10 min in portions and the resulting mixture was stirred at 0 ℃ for 30 min, then gradually warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with aqueous sodium thiosulfate (27.6mmol) and sodium bicarbonate (52.1mmol) to give a gummy mixture suspended in a slightly basic solution. The mixture was filtered and washed thoroughly with DCM to give a biphasic filtrate. The separated aqueous phase was extracted three times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 0-35% EtOAc/heptane) to afford E31-2 as a crystalline solid after concentration of the pure fractions under reduced pressure (1.97g, 91%).

Step 3.1-Ethyl-5- (4-hydroxyphenyl) -1H-imidazole-2-carbaldehyde (E31-3)

The title compound was prepared according to the procedure described for the construction of block E12 in example 7.7, step 1, starting from E31-2 and (4-hydroxyphenyl) boronic acid.

Steps 4 to 5.4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-ethyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzaldehyde (E31)

The title compound was prepared starting from E31-3 according to the procedure described for the construction of block E12 in example 7.7, steps 1 and 2.

Example 7.19: synthesis of 4-chloro-2- ((5- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-2-yl) oxy) benzaldehyde (E34)

Step 1.2- ((5-bromopyridin-2-yl) oxy) -4-chlorobenzaldehyde E34-1

To a mixture of 4-chloro-2-hydroxybenzaldehyde (5g, 31.9mmol), cesium carbonate (10.41g, 31.9mmol) and DMF (30mL) in a thick-walled glass vessel was added 5-bromo-2-fluoropyridine (6.74g, 38.3mmol) at room temperature. The resulting mixture was then flushed with nitrogen, sealed, and heated at 110 ℃ for 17 hours. The reaction mixture was cooled to room temperature, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 0-20% acetone/heptane) to yield E34-1(7.6g, 85% purity, 65%) after concentration of the pure fractions under reduced pressure.

Step 2.(6- (5-chloro-2-formylphenoxy) pyridin-3-yl) boronic acid E34-2

Bis (pinacol) diboron (5.41g, 21.31mmol), E34-1(3.33g, 10.65mmol), Pd (dppf) Cl₂A mixture of (0.870g, 1.07mmol) and KOAc (2.091g, 21.31mmol) in dry dioxane (30mL) was flushed three times with nitrogen. The resulting mixture was heated at 100 ℃ for 3 hours under nitrogen atmosphere, then filtered and concentrated. The crude product was purified by reverse phase column chromatography (C18, using 20-70% MeCN/water, 0.1% NH) ₄OH elution) and concentration of the pure fractions under reduced pressure gave E34-2 as boronic acid (1.22g, 41%).

(5-bromo-1-methyl-1H-imidazol-2-yl) methanol E34-3

To a solution of 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (2g, 10.58mmol) in MeOH (30mL) cooled in an ice bath was added sodium borohydride (0.801g, 21.16mmol) in portions. The resulting mixture was stirred in an ice bath for 60 minutes, then quenched with water and MeOH at 0 ℃ and concentrated to dryness in vacuo. The resulting residue was purified by flash chromatography (eluting with 0-40% DCM/MeOH) to afford E34-3(2g, quantitative yield) after concentration of the pure fractions under reduced pressure.

Step 3.4-chloro-2- ((5- (2- (hydroxymethyl) -1-methyl-1H-imidazol-5-yl) pyridin-2-yl) oxy) benzaldehyde E34-4

To a mixture in a microwave vial containing E34-3(0.392g, 2.054mmol), E34-2(0.38g, 1.370mmol) and dioxane (6mL) and flushed with nitrogen was added Pd (OAc)₂A pre-mixed solution of (0.031g, 0.137mmol) and (4- (N, N-dimethylamino) phenyl) di-tert-butylphosphine (APhos, 0.087g, 0.329mmol) in 2mL dioxane (flushed with nitrogen) was added followed by potassium carbonate (1.2M aqueous solution, 3.42mL, 4.11 mmol). The resulting mixture was flushed with nitrogen three times and heated at 120 ℃ for 16 hours. The reaction mixture was filtered and the filtrate was purified by reverse phase column chromatography (using 50-100% MeCN/water, 0.1% NH) ₄OH elution) and the pure fraction was concentrated under reduced pressure to give E34-4(120mg, 26%).

Step 4.4-chloro-2- ((5- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-2-yl) oxy) benzaldehyde E34

To a solution of E34-4(110mg, 0.320mmol) and DIPEA (0.140mL, 0.800mmol) in anhydrous DCM (3mL) at 0 deg.C was added methanesulfonyl chloride (0.037mL, 0.480mmol), and the resulting mixture was stirred at room temperature for 1 hour. Dimethylamine (130mg, 1.600mmol) in DMF (2mL) was then added, and the reaction mixture was stirred at rt overnight, then directly passed through reverse phase column chromatography (with MeCN/water, 0.1% NH₄OH elution) to yield E34(50mg, 42%) after concentration of the pure fractions.

Example 7.20: synthesis of 4-chloro-2- (4- (2- ((ethyl (1-methylcyclopropyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzaldehyde (E36)

Step 1.4- (1-methyl-2- (((1-methylcyclopropyl) amino) methyl) -1H-imidazol-5-yl) phenol E36-1

To a mixture of E3-1(500mg, 2.47mmol), 1-methylcyclopropylamine (266mg, 2.47mmol) in MeOH (30mL) was added DIPEA (0.864mL, 4.95 mmol). The resulting mixture was stirred at room temperature for 2 hours, then cooled using an ice bath. Add NaBH in small portions ₄(131mg, 3.46mmol) and the reaction mixture was warmed to room temperature for 1 hour with stirring and then concentrated under reduced pressure. The crude product was taken up in water and extracted twice with EtOAc. The separated organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a solid. The solid was taken up in 1:1 ACN/water and then lyophilized to give E36-1 as a beige solid (570mg, 90%), which was used in the next step without further purification.

Step 2.4- (2- ((ethyl (1-methylcyclopropyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenol (E36-2)

A mixture of acetaldehyde (924mg, 20.98mmol) and E36-1(270mg, 1.049mmol) in anhydrous MeOH (5mL) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (1.6g, 7.34mmol) was added and stirring was continued for another 1 hour. The reaction mixture was concentrated and EtOAc (100mL) was added. The organic phase was washed with water (2 × 50mL), brine (50mL), dried over sodium sulfate, filtered and concentrated to give E36-2(0.30g, 100% yield) which was used in the next step without purification.

Step 3.4-chloro-2- (4- (2- ((ethyl (1-methylcyclopropyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzaldehyde (E36)

The title compound E36 was prepared according to the procedure described for the construction of block E12 in example 7.7, step 2, starting from E36-2 and 4-chloro-2, 6-difluorobenzaldehyde.

The following intermediates in table 7A were prepared according to the procedures described herein above, using the appropriate starting materials, unless otherwise indicated.

Table 7A:

example 8: other building blocks and compounds

The experimental procedure described in examples 8 and 9 below can be used to synthesize linear and corresponding cyclic peptides. The linear peptide can be assembled in solid phase and in solution. The building blocks used for the synthesis are summarized in examples 1-7 above and example 8 below.

Example 8.1: synthesis of tert-butyl (R) -3- ((S) -3- ((4-chloro-2- (4- (2- ((2- (2-ethoxyethoxy) ethoxy) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) -piperidine-1-carboxylic acid trifluoroacetate (104B)

Step 1.(S) -benzyl 2- ((chlorocarbonyl) oxy) -3-phenylpropionate (104A)

At 0 ℃ under N₂To a solution of (S) -benzyl 2-hydroxy-3-phenylpropionate (256mg, 1mmol) in THF (2mL) under an atmosphere was added 20% phosgene in toluene (3.00mL, 5.70mmol) and the resulting mixture was stirred for 26 hours and then allowed to warm to room temperature. Additional 20% phosgene in toluene (1.997mL, 3.80mmol) was added and stirring continued for 3 days at room temperature for 22 hours. The reaction mixture was concentrated to dryness in vacuo to afford 104A as a pale yellow oil (297mg, 0.932mmol, 93% yield). The crude product was used in the next step without purification.

Step 2. tert-butyl (R) -3- ((S) -3- ((4-chloro-2- (4- (2- ((2- (2-ethoxyethoxy) ethoxy) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidine-1-carboxylic acid trifluoroacetate (104B)

Step 2-1: DIEA (0.070mL, 400. mu. mol) and 104A (49.4mg, 155. mu. mol) were added to 60B (100. mu. mol) dissolved in DCM (4mL), and the resulting mixture was stirred at room temperature for 90 min.

Step 2-2: diethylene glycol ethyl ether (26.8mg, 200. mu. mol) was added to the mixture from step 2-1, and the resulting mixture was stirred at room temperature for 16 hours. Additional diethylene glycol ethyl ether (26.8mg, 200. mu. mol) was added and stirring was continued at 45 ℃ for 23 h. Diethylene glycol ethyl ether (215mg, 1600. mu. mol) was added and stirring was continued at 45 ℃ for 3 days 23 hours. The reaction mixture was then concentrated in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give 104B as a white solid (29mg, 24.3 μmol, 24% yield). Analytical method 9; t is t_R＝4.57min；[M+H]⁺＝965.3。

Example 8.2: synthesis of t-butyl (S) -2-amino-4, 4-difluorobutanoic acid trifluoroacetate (58B)

Step 1. tert-butyl (S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4, 4-difluorobutanoate (58A)

To a solution of (S) -2- (Fmoc-amino) -4, 4-difluorobutanoic acid (361mg, 1mmol) in THF (10mL) was added tert-butyl 2,2, 2-trichloroacetimidate (0.537mL, 3.00mmol) and BF_3.OEt₂(0.025mL, 0.200 mmol). The resulting mixture was stirred at room temperature for 7 hours, then in EtOAc (60mL) and 5% NaHCO₃The aqueous solution (20mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous solution (2 × 10mL), 5% KHSO₄Aqueous solution (15mL) and brine (10mL) were washed with Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: heptane; eluent B: EtOAc). Pure fractions were combined and concentrated to dryness in vacuo to give 58A as a white solid (358mg, 0.858mmol, 86% yield). An analytical method 10; t is t_R＝1.33min；[M+Na]⁺＝440.2。

Step 2. tert-butyl (S) -2-amino-4, 4-difluorobutanoic acid trifluoroacetate (58B)

58A (356mg, 0.853mmol) is dissolved in 4-methylpiperidineDMA (1:4) (5mL)), stirred at room temperature for 45 minutes, then concentrated to dryness in vacuo. The crude product was passed through reverse phase flash chromatography (Teledyne ISCO; RediSep Rf Gold C18Aq column 20-40 μm 100 g; eluent A: H₂0.1% TFA in O; eluent B: 0.1% TFA in ACN). Pure fractions were combined and lyophilized to give 58B as a white solid (68.7mg, 0.222mmol, 26% yield). An analytical method 10; t is t _R＝0.43min；[M+H]⁺＝196.2。

Example 8.3: synthesis of (2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) -benzyl) -8- (4-chlorobenzyl) -12- ((R) -2, 3-dihydro-1H-inden-1-yl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone hydrochloride (Compound 86)

Step 1 PS-2-Chlorotriphenylmethyl (S) -4- (((R) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) (methyl) amino) -3- (4-chloro-phenyl) propyl) (methyl) amino) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoate (86A)

Step 1-1: PS-2-chlorotrityl chloride (653mg, 1.044mmol) was washed thoroughly with DCM. A solution of AB1(272mg, 0.418mmol) in DCM (10mL) and DIEA (0.365mL, 2.088mmol) was added to the resin and the suspension was shaken at room temperature for 3.5 h. The resin was then drained and washed thoroughly with DCM/MeOH/DIPEA (17:2:1), DCM and DMA in that order.

Step 1-2: 4-methylpiperidine/DMA (1:4) (4mL) was added to the resin and the resulting suspension was shaken at room temperature for 10 minutes and then drained. This treatment was repeated twice. The resin was washed with DMA (3X) and DCM (3X) and then dried in vacuo to give 86A (ca. 0.418 mmol).

Step 2 PS- (2-Chlorotriphenylmethyl) (S) -4- (((R) -2- ((S) -2-amino-3- (tert-butoxy) -N-methylpropanamide) -3- (4-chloro-phenyl) propyl) (methyl) amino) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoate (86B)

Step 2-1: with NMP(3X) Wash 86A (200. mu. mol). To Fmoc-Ser (tBu) -OH (230mg, 600. mu. mol) and PyOxim (316mg, 600. mu. mol) dissolved in NMP (2mL) was added DIEA (0.210mL, 1200. mu. mol), and the resulting solution was stirred at room temperature for 2 minutes, and then added to the resin. The suspension was shaken at room temperature for 17 hours. The resin was drained and then washed with DMA (3 ×). Addition of Ac₂O/pyridine/DMA (1:1:8) (2mL) and the reaction mixture was shaken at room temperature for 30 minutes. The resin was drained and then washed with DMA (3 ×).

Step 2-2: 4-methylpiperidine/DMA (1:4) (2mL) was added to the resin. The resulting suspension was shaken at room temperature for 10 minutes and then the resin was drained. This treatment was repeated twice. The resin was washed with DMA (3X) and DCM (3X). 86B was used directly in the next step.

Step 3 (S) -4- (((R) -2- ((S) -2- ((S) -2-aminopropionamide) -3- (tert-butoxy) -N-methylpropionamide) -3- (4-chloro-phenyl) propyl) (methyl) amino) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid (86C)

Step 3-1: 86B (200. mu. mol) was washed with NMP (3X). DIEA (0.210mL, 1200. mu. mol) was added to Fmoc-Ala-OH (187mg, 600. mu. mol) and PyOxim (316mg, 600. mu. mol) dissolved in NMP (2mL), and the resulting solution was stirred at room temperature for 2 minutes and then added to the resin. The suspension was shaken at room temperature for 2 h 15 min, the resin drained and then washed with DMA (3 ×). Addition of Ac ₂O/pyridine/DMA (1:1:8) (2mL), and the reaction was shaken at room temperature for 30 minutes. The resin was drained and then washed with DMA (3 ×).

Step 3-2: 4-methylpiperidine/DMA (1:4) (2mL) was added to the resin. The suspension was shaken at room temperature for 10 minutes and then the resin was drained. This treatment was repeated twice. The resin was washed with DMA (3X) and DCM (3X).

Step 3-3: HFIP/DCM (1:3) (3mL) was added to the resin in step 3-1 and the suspension was shaken at room temperature for 15 min. The lysis solution was filtered and collected. This procedure was repeated three times. Finally, the resin was washed once with HFIP/DCM (1:3) (1 mL). The combined cleavage and wash solutions were concentrated to dryness in vacuo to give 86C as an orange oil (about 200 μmol). The crude product was used without purification in the next stepAnd (5) one step. An analytical method 10; t is t_R＝0.95；[M+H]⁺＝643.4。

Step 4.(3S,6S,9R,13S) -6- (tert-butoxymethyl) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) phenyl) -9- (4-chlorobenzyl) -13- ((R) -2, 3-dihydro-1H-inden-1-yl) -3,8, 11-trimethyl-4, 7, 12-trioxa-2, 5,8, 11-tetraazapentadecane-15-oic acid trifluoroacetate (86D)

86C (200. mu. mol) and E2(95mg, 240. mu. mol) were dissolved in a mixture of DCM (12mL) and AcOH (0.046mL, 800. mu. mol) and stirred at room temperature for 90 min. Addition of NaBH (OAc) ₃(212mg, 1000. mu. mol), and the resulting mixture was stirred at room temperature for 19 hours and 15 minutes. MeOH (2mL) was added, and the mixture was concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give 86D as a white solid (127mg, 93 μmol, 47% over 4 steps). Analytical method 9; t is t_R＝4.41min；[M+H]⁺＝1022.4。

Step 5.(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) -benzyl) -8- (4-chlorobenzyl) -12- ((R) -2, 3-dihydro-1H-inden-1-yl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone hydrochloride (Compound 86)

Step 5-1: to 86D (127mg, 0.093mmol), HATU (141mg, 0.372mmol) and HOAt (18.99mg, 0.140mmol) was added DCM (93 mL). The resulting mixture was stirred at room temperature for 5 minutes, then 2, 6-lutidine (0.325mL, 2.79mmol) was added and stirring continued at 40 ℃ for 22 hours. Additional HATU (70.7mg, 0.186mmol) was added and stirring continued at 40 ℃ for 3 h. Oxyma Pure (13.22mg, 0.093mmol) was added. The reaction mixture was stirred at 40 ℃ for 4 hours and then concentrated to dryness in vacuo. The residue obtained was taken up in EtOAc (50mL) and 5% NaHCO ₃The aqueous solution (5mL) was partitioned. The organic phase was washed with 5% NaHCO₃(3X5mL) and brine (5mL) over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was used in the next step without purification.

Step 5-2: the residue from step 5-1 was dissolved in 95% aqueous TFA/DCM (1:1) (5mL) and the resulting solution was stirred at room temperature for 1 hour, then concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized. The product was dissolved in EtOAc (50mL) and the organic phase was washed with 5% NaHCO₃Aqueous (3X5mL) and brine (5mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. Dissolving the residue in ACN/H₂O (1:1) (20mL) and 0.1M aqueous HCl (3mL) was added. After lyophilization, compound 86 was obtained as a white solid (44.3mg, 0.042mmol, 45% yield). Analytical method 9; t is t_R＝5.10min；[M+H]⁺＝948.4

The compounds and intermediates shown in table 8 were synthesized from each of the intermediates shown in table 4, table 5, table 6 and table 7 according to the procedure described for compound 86 in example 8.3. For several compounds, no final deprotection step was performed.

Table 8: compounds prepared according to example 8.3 for Compound 86 and intermediates

Example 8.4: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (pyridin-3-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 19)

Step 1 PS-2-Chlorotriphenylmethyl (R) -4- ((R) -3-amino-3- (4-chlorobenzyl) piperidin-1-yl) -4-oxo-3- (pyridin-3-ylmethyl) -butanoate (19A)

Step 1-1: PS-2-chlorotrityl chloride (653mg, 1.044mmol) was washed thoroughly with DCM. AB14(0.856g, 1.115mmol) was dissolved in DCM (25mL) and DIEA (1.168mL, 6.69 mmol). The solution was added to the resin and the suspension was shaken at room temperature for 6 hours. The resin was drained and then washed thoroughly with DCM/MeOH/DIPEA (17:2:1), DCM, DMA and DCM in that order.

Step 1-2: 4-methylpiperidine/DMA (1:4) (20mL) was added to the resin of step 1-1. The suspension was shaken at room temperature for 5 minutes and then the resin was drained. This treatment was repeated four times. The collected lysis solution was used to determine the loading by uv spectroscopy. The resin was washed thoroughly with DMA (3X), DCM (3X), DMA (3X) and DCM (3X) in that order, and then dried in vacuo to give 19A (817. mu. mol, 73% yield).

Step 2.(R) -4- ((R) -3- ((S) -3- (L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxo-3- (pyridin-3-ylmethyl) butyric acid (19B)

Step 2-1: wash 19A (409 μmol) with NMP (2 × 10 mL). Fmoc-Ala-Ser [ psi (Me, Me) pro]A solution of-OH (C4) (0.323g, 736. mu. mol), HATU (0.280g, 736. mu. mol) and DIEA (0.157mL, 899. mu. mol) in NMP (8mL) was shaken for 2 minutes and then added to the resin. The resulting suspension was shaken at room temperature for 18 hours and then the resin was drained. Fmoc-Ala-Ser [ psi (Me, Me) pro]A solution of-OH (0.323g, 736. mu. mol), HATU (0.280g, 736. mu. mol) and DIEA (0.157mL, 899. mu. mol) in NMP (8mL) was shaken for 2 minutes and then added to the resin. The resulting suspension was shaken at room temperature for 18 hours. The resin was drained and washed with DMA (3 ×). Addition of Ac₂O/pyridine/DMA (1:1:8) (15mL), and the reaction was shaken at room temperature for 15 minutes. The resin was drained and then washed with DMA (3 ×).

Step 2-2: 4-methylpiperidine/DMA (1:4) (15mL) was added to the resin of step 2-1. The resulting suspension was shaken at room temperature for 10 minutes and then the resin was drained. This treatment was repeated twice. The resin was washed with DMA (3X) and DCM (5X).

Step 2-3: HFIP/DCM (1:3) (10mL) was added to the resin of step 2-2 and the suspension was shaken at room temperature for 20 min. The lysis solution was filtered and collected. This procedure was repeated twice. Finally, the resin was washed with DCM (2 ×). The combined cleavage and washing solutions were concentrated to dryness in vacuo and the resulting residue was taken up from t-BuOH/H₂O (4:1) was lyophilized to give 19B as a pale yellow solid (assumed to be 409. mu. mol). An analytical method 10; t is t_R＝0.70；[M+H]⁺＝614.3。

Step 3.(R) -4- ((R) -3- ((S) -3- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -benzyl) -L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxo-3- (pyridin-3-ylmethyl) butyric acid hydrochloride (19C)

19B (100. mu. mol) and E1(44.4mg, 120. mu. mol) were dissolved in a mixture of DCM (7mL) and AcOH (0.023mL, 400. mu. mol). The resulting solution was stirred at room temperature for 1 hour, then NaBH (OAc) was added₃(106mg, 500. mu. mol). The reaction mixture was stirred at room temperature for 2 hours and concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.01M HCl in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give 19C (75mg, 67 μmol, 67% over 2 steps). An analytical method 14; t is t _R＝2.84min；[M+H]⁺＝967.4。

Step 4.(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (pyridin-3-ylmethyl) -1,6,9, 12-tetraazabicyclo- [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 19)

Step 4-1: to a solution of 19C (75mg, 0.067mmol) in DCM (67ml) were added HOAt (13.75mg, 0.101mmol), HATU (102mg, 0.269mmol) and 2, 6-lutidine (0.235ml, 2.020 mmol). The resulting mixture was stirred at 40 ℃ for 17 hours and then concentrated in vacuo. The residue was taken up in EtOAc (100mL) and 5% Na₂CO₃The aqueous solution was partitioned. The organic phase was washed with 5% Na₂CO₃Aqueous solution (5mL) and brine, over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo.

Step 4-2: the residue was dissolved in 95% TFA/ACN/H₂O (2:5:3) aqueous solution and the resulting solution was stirred at room temperature for 45 minutes and then concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.01M HCl in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give compound 19 as a white solid (34.5mg, 0.030mmol, 45% yield). An analytical method 14; t is t_R＝2.97min；[M+H]⁺＝909.4。

The compounds and intermediates shown in table 9 were synthesized from each of the intermediates shown in table 4, table 5 and table 7 according to the procedure described for compound 19 in example 8.4.

Table 9: the compounds and intermediates prepared according to example 8.4 for compound 19.

Example 8.5: synthesis of (3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -7- (2-fluoroethyl) -10- (methoxymethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 105)

Step 1. (9H-fluoren-9-yl) methyl ((S) -1- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) amino) -3-methoxy-1-oxoprop-2-yl) carbamate (105A)

Step 1-1: to Fmoc-Ser (Me) -OH (0.683g, 2.000mmol) in DCM (10mL) was added Gauss reagent (0.265mL, 2.000 mmol). The resulting mixture was stirred at room temperature for 45 minutes, then a solution of B1(0.650g, 2.00mmol) and DIEA (0.419mL, 2.400mmol) in DCM (5mL) was added. The reaction mixture was stirred at room temperature for 5 h 40 min, then DIEA (0.105mL, 0.600mmol), and a solution of Fmoc-Ser (Me) -OH (0.137g, 0.400mmol) and Gauss reagent (0.053mL, 0.400mmol) in DCM (2mL) were added (preactivation time: 30 min). The resulting mixture was stirred at room temperature for 15 h 50 min, then in EtOAc (60mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO ₃(2X10mL) and brine (10mL) over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: heptane; eluent B: EtOAc). The pure fractions were combined and concentrated to dryness in vacuo to give a white foam (1.130g, 1.743mmol, 87% yield). Analysis methodMethod 10; t is t_R＝1.52min；[M+H]⁺＝648.4。

Step 1-2: the white foam from step 1-1 (1.743mmol) was dissolved in 95% TFA/DCM (1:1) in water (20 mL). The resulting solution was stirred at room temperature for 1 hour, then concentrated to dryness in vacuo to give 105A as a white foam (assumed to be 1.743 mmol). An analytical method 10; t is t_R＝0.94min；[M+H]⁺＝548.4。

Step 2.(R) -4- ((R) -3- ((S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutanoic acid (105B)

Step 2-1: a1(0.461g, 1.743mmol) and TBTU (0.588g, 1.831mmol) were dissolved in DCM (10mL) and DIEA (0.365mL, 2.092mmol) and stirred at room temperature for 30 min. A solution of 105A (1.743mmol) in DCM (10mL) and DIEA (0.761mL, 4.36mmol) was then added and the reaction mixture was stirred at room temperature for 3 hours, then DCM was removed in vacuo. The resulting residue was taken up in EtOAc (60mL) and 5% NaHCO₃The aqueous solution (15mL) was partitioned. The organic phase was washed with 5% NaHCO ₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dry, filter, and concentrate to dryness in vacuo to give a white foam. An analytical method 10; t is t_R＝1.57min；[M+H]⁺＝794.7。

Step 2-2: to a solution of step 2-1, white foam (1.74mmol) and 2, 6-lutidine (1.623mL, 13.94mmol) in DCM (20mL) was added TMSOTf (1.259mL, 6.97mmol) dropwise at 0 deg.C, and the resulting mixture was stirred at 0 deg.C for 3 h 50 min. Add EtOAc (60mL) and 5% NaHCO₃Aqueous solution (5mL) and the phases were separated. The organic phase was washed with 5% NaHCO₃Aqueous solution (3X5mL), 5% KHSO₄Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The resulting residue was dissolved in DCM and the solution was concentrated to dryness in vacuo to give 105B as a pale yellow foam (assumed to be 1.74 mmol). The crude product was used in the next step without further purification. An analytical method 10; t is t_R＝1.41min；[M+H]⁺＝738.4。

Step 3 PS-2-Chlorotriphenylmethyl (R) -4- ((R) -3- ((S) -2-amino-3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutyrate (105C)

Step 3-1: the PS-2-chlorotrityl chloride resin (2.72g, 4.36mmol) was washed with DCM (3X). A solution of 105B (1.742mmol) in DCM (20mL) and DIEA (1.825mL, 10.45mmol) was added to the resin, and the resulting suspension was shaken at room temperature for 15 h. The resin was drained and then washed thoroughly with DCM/MeOH/DIPEA (17:2:1) (3X), DCM (3X) and DMA (2X) in that order.

Step 3-2: 4-methylpiperidine/DMA (1:4) (20mL) was added to the resin from step 3-1. The resulting suspension was shaken at room temperature for 10 minutes and then the resin was drained. This treatment was repeated twice. The resin was washed with DMA (3X) and DCM (3X) and dried in vacuo to give 105C (1.32mmol, 66% yield over 3 steps) (3.65 g; 0.361mmol/g loading by UV spectroscopy).

Step 4.(R) -4- ((R) -3- ((S) -2- ((S) -2-amino-4-fluorobutanamide) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutanoic acid (105D)

Step 4-1: to a solution of D5(0.103g, 300. mu. mol) in NMP (3mL) were added HATU (0.114g, 300. mu. mol) and DIEA (0.058mL, 330. mu. mol). The resulting solution was stirred at room temperature for 2 minutes and then added to resin 105C (after washing with NMP (3 ×)). The resulting suspension was shaken at room temperature for 21 hours. The resin was drained and washed with DMA (3 ×). Addition of Ac₂A solution of O/pyridine/DMA (1:1:8) (3mL) was added and the reaction mixture was shaken at room temperature for 15 minutes. The resin was drained and then washed with DMA (3 ×).

Step 4-2: 4-methylpiperidine/DMA (1:4) (3mL) was added to the resin of step 4-1. The resulting suspension was shaken at room temperature for 10 minutes and then the resin was drained. This treatment was repeated twice. The resin was washed with DMA (3X) and DCM (3X).

Step 4-3: HFIP/DCM (1:3) (3mL) was added to the resin of step 4-2 and the resulting suspension was shaken at room temperature for 20 min. The lysis solution was filtered and collected. This procedure was repeated twice. The resin was then washed with DCM (2 ×), and the combined cleavage and washing was performedThe solution was concentrated to dryness in vacuo. The crude residue was dissolved in DCM and the resulting solution was concentrated to dryness in vacuo. This procedure was repeated three times. After drying using high vacuum, 105D (about 100. mu. mol) was obtained as a colorless oil. The crude product was used in the next step without further purification. An analytical method 10; t is t_R＝0.85；[M+H]⁺＝619.5。

Step 5.(R) -3-benzyl-4- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) -4-fluorobutanamide) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutanoic acid hydrochloride (105E)

105D (0.100mmol) and E1(44.6mg, 0.120mmol) were dissolved in a mixture of DCM (7mL) and AcOH (0.023mL, 0.402 mmol). The resulting solution was stirred at room temperature for 1 hour, then NaBH (OAc) was added₃(106mg, 0.502 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H) ₂0.01M HCl in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give 105E as a white solid (93mg, 0.086mmol, 86% yield). An analytical method 10; t is t_R＝0.90min；[M+H]⁺＝972.7。

Step 6((3R, 7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -7- (2-fluoroethyl) -10- (methoxymethyl) -1,6,9, 12-tetraazabicyclo- [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (compound 105)

To a solution of 105E in DCM (81mL) and NMP (5mL) were added HOAt (17.54mg, 0.129mmol), HATU (131mg, 0.344mmol), and 2, 6-lutidine (0.300mL, 2.58 mmol). The resulting mixture was stirred at 40 ℃ for 22 hours and then concentrated in vacuo. The residue obtained was in EtOAc (50mL) and 5% Na₂CO₃The aqueous solution (5mL) was partitioned. The organic phase was washed with 5% Na₂CO₃Aqueous (3X5mL) and brine (5mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.01M HCl in O; eluentB: ACN) is purified. Pure fractions were combined and lyophilized to give compound 105 as a white solid (50.5mg, 0.048mmol, 56% yield). An analytical method 14; t is t _R＝5.29min；[M+H]⁺＝954.4。

The compounds and intermediates shown in table 10 were synthesized from each of the intermediates shown in table 1, table 3, table 5, table 6 and table 7 according to the procedure described for compound 105 in example 8.5.

Table 10: the compound prepared according to example 8.5 for compound 105 and intermediates.

Example 8.6: synthesis of (3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 8, 11-trione trifluoroacetate (Compound 120)

Step 1.(R) -3-benzyl-4- ((R) -3- ((S) -2- ((S) -2- ((tert-butoxycarbonyl) amino) propionamide) -3-methoxypropan-amido) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutanoic acid (120A)

Step 1-1: to a solution of Boc-Ala-OH (0.057g, 300. mu. mol) in NMP (3mL) was added HATU (0.114g, 300. mu. mol) and DIEA (0.058mL, 330. mu. mol). The resulting solution was stirred at room temperature for 2 minutes and then added to 105C (100 μmol) (see example 8.5). The resulting suspension was shaken at room temperature for 21 hours. The resin was drained and then washed with DMA (3 ×). Addition of Ac₂O/pyridine/DMA (1:1:8) (3mL), and the reaction was shaken at room temperature for 15 minutes. The resin was drained and washed with DMA (x3) and DCM (x 3).

Step 1-2: HFIP/DCM (1:3) (3mL) was added to the resin of step 1-1 and the resulting suspension was shaken at room temperature for 20 min. The lysis solution is filtered andand (6) collecting. This procedure was repeated twice. The resin was then washed with DCM (2 ×), and the combined cleavage and wash solutions were concentrated to dryness in vacuo. The crude residue was dissolved in DCM and the resulting solution was concentrated to dryness in vacuo. This procedure was repeated three times. After drying using high vacuum, 120A (about 100. mu. mol) was obtained as a colorless oil. The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.24；[M+H]⁺＝687.4。

Step 2. Tert-butyl ((S) -1- (((S) -1- (((R) -1- ((R) -2-benzyl-4-hydroxybutyryl) -3- (4-chlorobenzyl) piperidin-3-yl) amino) -3-methoxy-1-oxoprop-2-yl) amino) -1-oxoprop-2-yl) carbamate (120B)

To 120A (100. mu. mol) in THF (4 mL). DIEA (0.026mL, 150. mu. mol) isobutyl chloroformate (0.014mL, 110. mu. mol) was added, and the resulting mixture was stirred at room temperature for 35 minutes. Additional DIEA (0.013mL, 75. mu. mol) and isobutyl chloroformate (7.22. mu.L, 55.0. mu. mol) were added and the reaction mixture was stirred at room temperature for 25 minutes and then cooled to-20 ℃. Addition of NaBH₄(7.57mg, 200. mu. mol) in diglyme (1mL) and the resulting mixture was stirred for 45 minutes and then allowed to warm to room temperature. Additional NaBH added in diglyme (1mL) ₄(7.57mg, 200. mu. mol), and the reaction mixture was stirred at room temperature for 45 minutes. Diethylene glycol dimethyl ether (5mL) and NaBH were added again₄(9.46mg, 250. mu. mol) and stirring was continued at room temperature for 2.5 hours. The reaction mixture was washed with EtOAc (50mL) and 5% NaHCO₃The aqueous solution (15mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dry, filter, and concentrate to dryness in vacuo to give 120B as a colorless paint (assumed to be 100 μmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.17min；[M+H]⁺＝673.7。

Step 3. Tert-butyl ((S) -1- (((S) -1- (((R) -1- ((R) -2-benzyl-4-hydroxybutyryl) -3- (4-chlorobenzyl) piperidin-3-yl) amino) -3-methoxy-1-oxoprop-2-yl) amino) -1-oxoprop-2-yl) carbamate (120C)

To 120B (0.100 m)mol) to a solution in DCM (10mL) was added dess-Martin periodinane (46.5mg, 0.110mmol), and the resulting mixture was stirred at room temperature for 2 h 45 min. Additional dess-martin periodinane (23.27mg, 0.055mmol) was added and stirring continued at room temperature for 2 hours 15 minutes. The reaction was quenched by the addition of 5% NaHCO₃Aqueous solution/20% Na₂S₂O₃Aqueous solution (1:1) (20mL) was quenched. EtOAc (50mL) was added and the phases were separated. The organic phase was washed with 5% NaHCO ₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave 120C as a pale yellow oil (assumed to be 0.100 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.26min；[M+H]⁺＝671.4。

Step 4.(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 8, 11-trione trifluoroacetate (compound 120)

Step 4-1: 120C (100. mu. mol) was dissolved in 95% aqueous TFA/DCM (1:1) (10mL), stirred at room temperature for 1 hour, and then concentrated to dryness in vacuo. The resulting residue was dissolved in toluene and concentrated to dryness. Treatment with toluene (1x) was repeated.

Step 4-2: the residue from step 4-1 was dissolved in DCM (10 mL). AcOH (0.011mL, 200. mu. mol), NaBH (OAc) were added₃(42.4mg, 200. mu. mol), and the reaction mixture was stirred at room temperature for 150 minutes.

Step 4-3: e1(55.5mg, 150. mu. mol) was added to the reaction mixture of step 4-2 and stirred at room temperature for 50 minutes. Addition of additional NaBH (OAc)₃(42.4mg, 200. mu. mol) and stirring was continued at room temperature for 4 hours and 20 minutes. Add M NaBH (OAc) again ₃(42.4mg, 200. mu. mol) and stirring was continued at room temperature for 18 h 50 min. DCM is removed in vacuo and the product is passed through preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) was isolated. The product containing fractions were combined and lyophilized to give compound 120 as a white solid (1.1mg, 0.572. mu. mol)Yield 0.6% in 4 steps). An analytical method 14; t is t_R＝4.13min,[M+H]⁺＝908.3。

Example 8.7: synthesis of (3S,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone trifluoroacetate (Compound 96)

Step 1. tert-butyl (3S) -4- (3- ((S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutyrate (96B)

A3(87mg, 0.300mmol) and HATU (125mg, 0.330mmol) were dissolved in DCM (6mL) and DIEA (0.063mL, 0.362 mmol). The resulting mixture was stirred at room temperature for 15 min and a solution of 96A (0.248mmol) (96A synthesized according to the method described for 105A starting from B8) in DCM (5mL) and DIEA (0.131mL, 0.748mmol) was added. The reaction mixture was stirred at room temperature for 67 h, then in EtOAc (50mL) and 5% NaHCO ₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 10mL) and brine (10mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave 96B (mixture of diastereomers; about 0.248mmol) as a colorless oil. The crude product was used in the next step without purification. An analytical method 10; t is t_R＝1.60min；[M+H]⁺＝820.6。

Step 2. tert-butyl (3S) -4- (3- ((S) -2-amino-3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutyrate (96C)

96B (0.248mmol) was dissolved in 4-methylpiperidine/DMA (1:4) (5mL) and the resulting solution was stirred at room temperature for 30 minutes and then concentrated to dryness in vacuo. The crude product was chromatographed on flash silica gel (eluent A: heptane/DIEA (98: 2); eluent B1: EtOAc/DIEAB2: EtOAc/MeOH/DIEA (100:5: 2)). The pure fractions were combined and concentrated to dryness in vacuo to give 96C as a yellow oil (diastereomer mixture; 128mg, 0.214mmol, 86% over 2 steps). An analytical method 10; t is t_R＝1.16/1.18min；[M+H]⁺＝598.5。

Step 3 (S) -4- ((R) -3- ((S) -2- ((S) -2-aminopropionamide) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutyric acid trifluoroacetate (96D)

Step 3-1: to Boc-Ala-OH (44.2mg, 0.234mmol) and TBTU (75.0mg, 0.234mmol) in DMF (3mL) was added DIEA (0.044mL, 0.255 mmol). The resulting mixture was stirred at room temperature for 5 minutes and a solution of 96C (127mg, 0.212mmol) in DMF (3mL) was added. The reaction mixture was then stirred at room temperature for 4 h 50 min in EtOAc (50mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo.

Step 3-2: the residue from step 3-1 was dissolved in 95% aqueous TFA/DCM (15mL), stirred at room temperature for 1 hour, and then concentrated to dryness in vacuo. The diastereoisomers were purified by preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) was isolated. Pure fractions were combined and lyophilized to give 96D as a white solid (43mg, 0.059mmol, 28% yield). An analytical method 10; t is t_R＝0.94min；[M+H]＝613.3。

Step 4.((S) -4- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) -phenoxy) benzyl) amino) propionamide) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid trifluoroacetate (96E)

96D (43mg, 0.059mmol) and E2(30.4mg, 0.077mmol) were dissolved in a mixture of DCM (5mL) and AcOH (0.014mL, 0.237 mmol). The solution was stirred at room temperature for 30 minutes, then NaBH (OAc) was added₃(25.07mg, 0.118 mmol). The reaction mixture was stirred at room temperature for 50 minutes, then additional E2(11.71mg, 0.030mmol) was added.After stirring at room temperature for 14.5 h, more E2(11.71mg, 0.030mmol) was added. The resulting mixture was stirred at room temperature for 80 minutes, and NaBH (OAc) was added again₃(25.07mg, 0.118mmol) and stirring was continued for 80 min. MeOH (1mL) was added, and the mixture was concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give 96E as an off-white solid (19.4mg, 0.015mmol, 25% yield). An analytical method 10; t is t_R＝1.00min；[M+H]⁺＝992.6。

Step 5.(3S,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) -benzyl) -13- (4-chlorobenzyl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone trifluoroacetate (Compound 96)

To 96E in DCM (14.4 mL). HATU (21.87mg, 0.058mmol) HOAt (2.94mg, 0.022mmol) was added, and the resulting mixture was stirred at room temperature for 5 minutes. Then 2, 6-lutidine (0.050mL, 0.431mmol) was added. The reaction mixture was stirred at 40 ℃ for 17 hours and concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H) ₂0.1% TFA in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give compound 96 as a white solid (8.4mg, 6.56 μmol, 46% yield). Analytical method 9; t is t_R＝5.52min；[M+H]⁺＝974.4。

Example 8.8: synthesis of (3S,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 4,6,9, 12-pentaza-bicyclo [11.3.1] -heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 60)

Step 1.(R) -tert-butyl 3- ((S) -2-aminopropionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chloro-benzyl) piperidine-1-carboxylate (60A)

Step 1-1: to Fmoc-Ala-Ser [ psi (Me, Me) pro]DIEA (0.227mL, 1300. mu. mol) was added to a solution of-OH (438mg, 1000. mu. mol) and HATU (399mg, 1050. mu. mol) in DMA (5 mL). The resulting solution was stirred at room temperature for 2 minutes and then added to a solution of B2(325mg, 1000. mu. mol) in DMA (5 mL). The reaction mixture was stirred at room temperature for 4 hours and 40 minutes. Additional Fmoc-Ala-Ser [ psi (Me, Me) pro ] in DMA (1mL) was added]OH (132mg, 300. mu. mol), HATU (133mg, 350. mu. mol) and DIEA (0.070mL, 400. mu. mol) (preactivation time: 2 min) and stirring was continued at room temperature for 16 h 20 min. The reaction mixture was purified in EtOAc (70mL) and 5% NaHCO ₃The aqueous solution (15mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo.

Step 1-2. the residue from step 1-1 was dissolved in DMA/4-methylpiperidine (4:1) (10mL), stirred at room temperature for 30 minutes, and then concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: EtOAc/DIEA (98: 2); eluent B: EtOAc/MeOH/DIEA (90:10: 2)). The pure fractions were combined and concentrated to dryness in vacuo to give 60A as a white solid (465mg, 889 μmol, 89% yield). An analytical method 10; t is t_R＝0.86min；[M+H]⁺＝523.3。

Step 2.(R) -tert-butyl 3- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (60B)

60A (465mg, 0.889mmol) and E1(362mg, 0.978mmol) were dissolved in a mixture of DCM (10mL) and AcOH (0.204mL, 3.56mmol) and stirred at room temperature for 45 min. Addition of NaBH (OAc)₃(942mg, 4.44mmol) and the reaction mixture was stirred at room temperature for 2 h, then in EtOAc (70mL) and 5% Na₂CO₃The aqueous solution (20mL) was partitioned. The organic phase was washed with 5% Na ₂CO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Drying, filtering, and vacuum concentrating to dryness to give a pale beige foam60B (assumed to be 0.889 mmol). The crude product was used in the next step without purification. An analytical method 10; t is t_R＝0.86min；[M+H]⁺＝876.6。

Step 3 (S) -2- (3- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -3- ((S) -1- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) amino) -3-hydroxy-1-oxoprop-2-yl) amino) -1-oxoprop-2-yl) ureido) -3-phenylpropionic acid hydrochloride (60C)

Step 3-1 (S) -tert-butyl 2-amino-3-phenylpropionate HCl (38.7mg, 150. mu. mol) was dissolved in DCM (2mL) and DIEA (0.052mL, 300. mu. mol). 4-Nitrophenyl chloroformate (30.2mg, 150. mu. mol) was added, and the reaction mixture was stirred at room temperature for 90 minutes.

Step 3-2. A solution of 60B (100. mu. mol) in DCM (2mL) and DIEA (0.026mL, 150. mu. mol) was added to the mixture of step 3-1. The resulting mixture was stirred at room temperature for 20.5 h and in EtOAc (40mL) and 5% NaHCO₃The aqueous solution (7mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (4X7mL) and brine (5mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo.

Step 3-3. the residue from step 3-2 was dissolved in 95% aqueous TFA (5mL), stirred at room temperature for 1 hour, and then concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H) ₂0.01M HCl in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give 60C as a white solid (52mg, 50.1 μmol, 50% over 2 steps). An analytical method 14; t is t_R＝3.43min；[M+H]⁺＝927.3。

Step 4.(3S,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 4,6,9, 12-pentazabicyclo [11.3.1] -heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 60)

To 60C (52mg, 0.050mmol) in DCM (50mL) was added HATU (76mg, 0.201mmol) and HOAt (10.23mg, 0.075 mmol). After stirring at room temperature for 10 minutes, 2, 6-lutidine (0.175mL, 1.504mmol) was added and the mixture was stirredThe reaction mixture was stirred at room temperature for 2.5 hours, then concentrated to dryness in vacuo. The residue was taken up in EtOAc (40mL) and 5% NaHCO₃The aqueous solution (5mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (3X5mL) and brine (5mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.01M HCl in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give compound 60 as a white solid (27.1mg, 0.027mmol, 55% yield). An analytical method 14; t is t _R＝4.49min；[M+H]⁺＝909.3。

The compounds and intermediates shown in table 11 were synthesized according to the procedure described for compound 60 in example 8.8.

Table 11: compounds prepared according to example 8.8 for Compound 60 and intermediates

Compound 104 was synthesized starting from 104B according to the procedure described for compound 60 in example 8.8.

Example 8.9: synthesis of (3S,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-4-oxa-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 78)

Step 1.(S) -2- ((((S) -1- ((S) -4- (((R) -1- (tert-butoxycarbonyl) -3- (4-chlorobenzyl) piperidin-3-yl) carbamoyl) -2, 2-dimethyloxazolidin-3-yl) -1-oxopropan-2-yl) (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) carbamoyl) oxy) -3-phenylpropionic acid trifluoroacetate (78A)

Step 1-1: to 60B (100. mu. mol) dissolved in DCM (1mL) was added a solution of 104A (159mg, 500. mu. mol) in DCM (1mL) and DIEA. The resulting mixture was stirred at room temperature for 4 hours.

Step 1-2: 33% Me in EtOH₂NH (0.143mL, 800. mu. mol) was added to the mixture from step 1-1 and stirring was continued at room temperature for 42.5 h. The reaction mixture was concentrated in vacuo, and the residue was taken up in EtOAc (40mL) and 5% NaHCO ₃The aqueous solution (5mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2X5mL) and brine (5mL) and washed with Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo.

Step 1-3: to a solution in NMP (6mL) and H₂To the residue from step 1-2 in O (0.9mL) was added 4M NaOH (0.100mL, 400. mu. mol), and the resulting mixture was stirred at room temperature for 4 hours 45 minutes. Addition of additional H₂O (1.9mL) and 4M NaOH (0.100mL, 400. mu. mol) and stirring was continued for 17 hours. 1M NaOH (0.500mL, 500. mu. mol) was again added, and the reaction mixture was stirred at room temperature for 22.5 hours. Additional 1M NaOH (0.500mL, 500 μmol) was added, and the reaction mixture was stirred at room temperature for 9 hours, quenched by the addition of AcOH (0.1mL), and concentrated in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give 78A as a white solid (38.9mg, 30.0 μmol, 30% yield). Analytical method 9; t is t_R＝5.81min；[M+H]⁺＝1068.4。

Step 2.(3S,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) -phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-4-oxa-1, 6,9, 12-tetraazabicyclo [11.3.1] -heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 78)

Step 2-1: 78A (38.9mg, 0.030mmol) was dissolved in 95% aqueous TFA (5mL), stirred at room temperature for 1 hour, and then concentrated to dryness in vacuo.

Step 2-2: to the residue from step 2-1 dissolved in DCM (30mL) was added HOAt (6.12mg, 0.045mmol) and HATU (45.6mg, 0.120mmol), and the resulting mixture was stirred at room temperature for 5 min. 2, 6-lutidine (0.105mL,0.900mmol) and the reaction mixture was stirred at room temperature for 2 hours 15 minutes and then concentrated to dryness in vacuo. The residue obtained was taken up in EtOAc (40mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.01M HCl in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give compound 78(11.3mg, 0.011mmol, 38% yield) as a white solid. Analytical method 9; t is t_R＝4.71min；[M+H]⁺＝910.3。

Example 8.10: synthesis of ((3S,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-4-oxa-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 156)

Step 1. tert-butyl (R) -3- ((S) -2-amino-3-methoxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (156A)

Step 1-1 Gauss reagent (0.095mL, 720. mu. mol) was added to Fmoc-Ser (Me) -OH (246mg, 720. mu. mol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 45 minutes, then a solution of B2(195mg, 600. mu. mol) and DIEA (0.157mL, 900. mu. mol) in DCM (2mL) was added. The reaction mixture was stirred at room temperature for 90 minutes and DCM was removed in vacuo.

Step 1-2 to the residue from step 1-1 dissolved in THF (5mL) and NMP (4mL) was added 0.5M NaOH aqueous solution (3.6mL, 1800. mu. mol) and the resulting mixture was stirred at room temperature for 2 hours. THF was removed in vacuo and the residue was taken up in EtOAc (50mL) and 5% Na₂CO₃The aqueous solution (5mL) was partitioned. The organic phase was washed with 5% Na₂CO₃Aqueous (2 × 5mL) and brine (10mL) were washed over Na₂SO₄Drying, filtering, and vacuum concentrating to obtainAnd (5) drying. The crude product was purified by flash chromatography on silica gel (eluent A: EtOAc/DIEA (98: 2); eluent B: EtOAc/MeOH/DIEA (85:15: 2)). The pure fractions were combined and concentrated to dryness in vacuo to give 156A (about 600 μmol) as a yellow oil. The product was used in the next step without further purification. An analytical method 10; t is t _R＝0.77min；[M+H]⁺＝426.3。

Step 2 tert-butyl (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -L-alanine ester (156B)

To E1(534mg, 1.444mmol) and (S) -tert-butyl 2-aminopropionate HCl (393mg, 2.166mmol) was added a mixture of DCM (20mL) and AcOH (0.331mL, 5.78 mmol). The resulting solution was stirred at room temperature for 80 minutes, then NaBH (OAc) was added₃(1530mg, 7.22 mmol). The reaction was stirred at rt for 14.5 h, DCM was removed and the residue was taken up in EtOAc (50ml) and 5% Na₂CO₃The aqueous solution (30mL) was partitioned. The organic phase was washed with 5% Na₂CO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: EtOAc/DIEA (98: 2); eluent B: EtOAc/MeOH/DIEA (90:10: 2)). The pure fractions were combined and concentrated to dryness in vacuo to give 156B as a yellow oil (347mg, 0.695mmol, 48% yield). An analytical method 10; t is t_R＝0.59min,[M+H]⁺＝499.5。

Step 3 benzyl (S) -2- ((((S) -1- (tert-butoxy) -1-oxopropan-2-yl) (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) carbamoyl) oxy) -3-phenylpropionate (156C)

Step 3-1: to a solution of 156B (278mg, 0.557mmol) in DCM (5mL) and DIEA (0.389mL, 2.228mmol) was added 104A (408mg, 1.281 mmol; see example 8.9) in DCM (4 mL). The reaction mixture was stirred at room temperature for 1h 45 min, additional 104A (98mg, 0.306mmol) in DCM (1mL) was added and stirring continued for 90 min.

Step 3-2: 33% dimethylamine in EtOH (0.796mL, 4.46mmol) was added to the mixture from step 3-1. Will be describedThe resulting mixture was stirred at room temperature for 18 hours, then concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica gel (eluent A: EtOAc/DIEA (98: 2); eluent B: EtOAc/MeOH/DIEA (90:10: 2)). The pure fractions were combined and concentrated to dryness in vacuo to give 156C as a yellow oil (362mg, 0.463mmol, 83% yield). An analytical method 10; t is t_R＝1.13min；[M+H]⁺＝781.5。

Step 4 benzyl (S) -2- ((((S) -1- (tert-butoxy) -1-oxopropan-2-yl) (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) carbamoyl) oxy) -3-phenylpropionate (156D)

156C (362mg, 0.463mmol) was dissolved in 95% aqueous TFA/DCM (1:1) (10 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to dryness in vacuo to give 156D as a yellow oil (assumed to be 0.463mmol), which was used in the next step without purification. An analytical method 10; t is t_R＝0.95min；[M+H]⁺＝725.4。

Step 5 (4S,7S,11S) -11-benzyl-8- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -4- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) carbamoyl) -7-methyl-6, 9-dioxo-2, 10-dioxa-5, 8-diaza-dodecane-12-oic acid hydrochloride (156E)

Step 5-1: to 156D (463. mu. mol) and TBTU (223mg, 695. mu. mol) were added DCM (10mL) and 2, 6-lutidine (1.079mL, 9260. mu. mol). The resulting mixture was stirred at room temperature for 5 minutes, then a solution of 156A (230mg, 486. mu. mol) in DCM (10mL) was added. The reaction mixture was stirred at room temperature for 160 minutes and DCM was removed in vacuo. The residue was taken up in EtOAc (50mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo to afford a yellow oil. An analytical method 10; t is t_R＝1.24min；[M+H]⁺＝1132.3。

Step 5-2: the residue from step 5-1 (448mg, 0.395mmol) was slowly dissolved in 33% wt HBr in AcOH (20mL) and DCM (10 mL). The resulting mixture was stirred at room temperature for 2 hours, and thenConcentrate to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.01M HCl in O; eluent B: ACN) is purified. After lyophilization, 156E-Lot 1 was obtained as a white solid (89.8mg, 0.085mmol, 18% yield for step 5 and step 6), and 156E-Lot 2 was obtained as an off-white solid (63.4mg, 0.060mmol, 13% yield for step 5 and step 6). An analytical method 14; t is t_R＝4.02min；[M+H]⁺＝942.3。

Step 6.(3S,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) -phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-4-oxa-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 156)

The cyclization of 156E is divided into two portions. Part 1: to a solution of 156E-batch 1(89.4mg, 0.085mmol) in DCM/NMP (14:3) (85mL) was added HOAt (52.0mg, 0.382mmol) and HATU (129mg, 0.340 mmol). The resulting mixture was stirred at room temperature for 5 minutes, then 2, 6-lutidine (0.297mL, 2.55mmol) was added. The reaction mixture was stirred at room temperature for 90 minutes and then concentrated to dryness in vacuo. The residue was taken up in EtOAc (50mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous solution (2 × 10mL) and brine, washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo.

Part 2: to a solution of 156E-batch 2(63.0mg, 0.060mmol) in DCM/NMP (53:10) (63mL) was added HOAt (36.7mg, 0.269mmol) and HATU (91mg, 0.239 mmol). The resulting mixture was stirred at room temperature for 5 minutes, then 2, 6-lutidine (0.209mL, 1.796mmol) was added. The reaction mixture was stirred at room temperature for 90 minutes and concentrated to dryness in vacuo. The residue was taken up in EtOAc (50mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous solution (2 × 10mL) and brine, washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo.

The crude product is passed through preparative reverse phase HPLC (eluent A: H) ₂0.01M HCl in O; eluent B: ACN) is purified. The pure fractions were combined and lyophilized to give a white solidCompound 156(55.6mg, 0.055mmol, 38% yield) as a colored solid. An analytical method 14; t is t_R＝5.23min；[M+H]⁺＝924.3。

Example 8.11: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -3-isopropyl-7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 133)

Step 1. tert-butyl (R) -3- ((S) -3- (N- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) -phenoxy) benzyl) -N- ((R) -3- (methoxycarbonyl) -4-methylpentanoyl) -L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (133A)

(R) -3- (methoxycarbonyl) -4-methylpentanoic acid (A12, 20.90mg, 120. mu. mol) and HATU (45.6mg, 120. mu. mol) were dissolved in DCM (1mL) and DIEA (0.026mL, 150. mu. mol) and stirred at room temperature for 30 min. A solution of 60B (100. mu. mol) in DCM (3mL) was then added and the resulting mixture was stirred at room temperature for 2 hours, then at 40 ℃ for 2 hours. Additional DIEA (0.026mL, 150. mu. mol) was added and stirring was continued at 40 ℃ for 17.5 hours. A solution of (R) -3- (methoxycarbonyl) -4-methylpentanoic acid (20.90mg, 120. mu. mol) and PyOxim (68.6mg, 130. mu. mol) in DCM (1mL) and DIEA (0.026mL, 150. mu. mol) was added (preactivation time 2 min) and the reaction mixture was stirred at room temperature for 32 h. An additional solution of (R) -3- (methoxycarbonyl) -4-methylpentanoic acid (41.8mg, 240. mu. mol) and HATU (91mg, 240. mu. mol) in DCM (1mL) and DIEA (0.052mL, 300. mu. mol) was added (preactivation time 20 min) and stirring was continued at room temperature for 88 h. The reaction mixture was dissolved in EtOAc (50mL) and 5% Na ₂CO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% Na₂CO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Dried, filtered and concentrated to dryness in vacuo to give 133A (ca. 100. mu. mol) as a brown oil, which was concentrated to drynessIt was used in the next step without purification. An analytical method 10; t is t_R＝1.20min；[M+H]⁺＝1032.5。

Step 2.(S) -4- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) ((S) -1- (((S) -1- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) amino) -3-hydroxy-1-oxoprop-2-yl) amino) -2-isopropyl-4-oxobutanoic acid hydrochloride (133B)

Step 2-1: to 133A (0.100mmol) in THF (5mL) was added 0.25M NaOH aqueous solution (2.000mL, 500. mu. mol), and the resulting mixture was stirred at room temperature for 90 minutes. Additional 0.25M NaOH aqueous solution (2.000mL, 500. mu. mol) was added and stirring continued at room temperature for 2 hours. Aqueous 2m naoh (0.500mL, 1000 μmol) was added again and the reaction mixture was stirred at room temperature for 2 hours. Additional aqueous 2M NaOH (0.500mL, 1000. mu. mol) and NMP (2mL) were added and stirring was continued at room temperature for 16 hours, followed by stirring at 45 ℃ for 4 days 23.5 hours. The reaction mixture was quenched with AcOH (0.115mL, 2.001mmol) and THF was removed in vacuo. The residue was washed with EtOAc (50mL) and H ₂Partition between O (5 mL). The organic phase was washed with 5% NaHCO₃Washed (5mL) with brine (5mL) over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo.

Step 2-2: the residue from step 2-1 was dissolved in 95% aqueous TFA (7mL) and DCM (3mL), stirred at rt for 1h, then concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.01M HCl in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give 133B as a white solid (16mg, 0.016mmol, 16% over 2 steps). An analytical method 14; t is t_R＝3.37min；[M+H]⁺＝878.4。

Step 3.(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -3-isopropyl-7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] -heptadecane-2, 5,8, 11-tetraone hydrochloride (compound 133)

To 133B (16mg, 0.016mmol) in DCM/NMP (3:1) (16mL) was added HATU (24.62mg, 0.065mmol)And HOAt (3.31mg, 0.024 mmol). The resulting mixture was stirred at room temperature for 10 minutes, then 2, 6-lutidine (0.057mL, 0.486mmol) was added. The reaction mixture was stirred at room temperature for 15 h, additional HATU (6.16mg, 0.016mmol) was added, and stirring was continued for 2 h. The reaction mixture was concentrated in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H) ₂0.01M HCl in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized to give compound 133 as a white solid (9.1mg, 9.55 μmol, 59% yield). Analytical method 9; t is t_R＝4.63min；[M+H]⁺＝860.4。

Example 8.12: synthesis of (3S,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 68)

Step 1 methyl (S) -4- ((R) -3- ((S) -3- (L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) -piperidin-1-yl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutyrate trifluoroacetate (68A)

Step 1-1: to a solution of Fmoc-Ala-Ser [ psi (Me, Me) pro ] -OH (119mg, 0.270mmol) and HATU (103mg, 0.270mmol) in DMA (2mL) was added DIEA (0.061mL, 0.351 mmol). The resulting solution was stirred at room temperature for 2 minutes, then a solution of AB17(123mg, 0.270mmol) in DMA (3mL) was added. The reaction mixture was stirred at room temperature for 3.5 hours.

Step 1-2: 4-methylpiperidine (1mL) was added to the mixture of step 1-1. The reaction mixture was stirred at room temperature for 30 minutes, then purified by the addition of AcOH (1.5mL) and H ₂O (2mL) quench. The resulting solution was directly subjected to preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN). Pure fractions were combined and lyophilized to give 68A as a white solid (120.6mg, 0.157mmol, 58.1% yield). An analytical method 10; t is t_R＝1.11；[M+H]⁺＝653.2。

Step 2 methyl (S) -4- ((R) -3- ((S) -3- ((4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutyrate (68B)

68A (120.0mg, 0.156mmol) and E2(74.3mg, 0.188mmol) were dissolved in a mixture of DCM (8mL) and AcOH (0.036mL, 0.626mmol) and stirred at room temperature for 1 hour. Addition of NaBH (OAc)₃(166mg, 0.782mmol) and the reaction mixture was stirred at room temperature for 16 h and then concentrated to dryness in vacuo. The resulting residue was taken up in EtOAc (50mL) and 5% Na₂CO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% Na₂CO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Drying, filtration, and concentration to dryness in vacuo gave 68B (159mg, 0.154mmol, 98% yield) as a beige foam. The product was used in the next step without purification. An analytical method 10; t is t _R＝1.11min；[M+H]⁺＝1032.3。

Step 3.(3S,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) -benzyl) -13- (4-chlorobenzyl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 68)

Step 3-1: to dioxane (8mL) and H₂To 68B (159mg, 0.154mmol) in O (2mL) was added 1M aqueous NaOH (0.616mL, 0.616 mmol). The resulting mixture was stirred at room temperature for 5.5 hours and then added to H₂Quench with 1M aqueous HCl (0.462mL, 0.462mmol) in O (0.92 mL). The reaction mixture was concentrated to dryness in vacuo to afford a beige solid. An analytical method 10; t is t_R＝1.05min；[M+H]＝1018.3。

Step 3-2: to a solution of the residue of step 3-1 (154. mu. mol) in DCM (154mL) were added HOAt (21.0mg, 154. mu. mol) and HATU (234mg, 616. mu. mol), and the resulting mixture was stirred at room temperature for 5 minutes. 2, 6-lutidine (0.53) was added8mL, 4620 μmol) and the reaction mixture was stirred at 40 ℃ for 19.5 hours and then concentrated to dryness in vacuo. The residue was taken up in EtOAc (50mL) and 5% NaHCO₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 10mL) and brine (10mL) were washed over Na ₂SO₄Dried, filtered, and concentrated to dryness in vacuo.

Step 3-3: dissolving the residue from step 3-2 in ACN/H₂O (5:3) (8mL) and 95% aqueous TFA (2mL) was added. The reaction was stirred at room temperature for 45 minutes and then concentrated to dryness in vacuo. The product was purified by preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized. The product (TFA salt) was dissolved in EtOAc (100mL) and the organic phase was washed with 5% NaHCO₃Aqueous (3X5mL) and brine (5mL) were washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. Dissolving the residue in ACN/H₂O (1:1) (40mL) and 0.1M aqueous HCl (4.5mL) was added. After lyophilization, compound 68 was obtained as a white solid (40.6mg, 38.1 μmol, 25% yield). Analytical method 9; t is t_R＝5.02min；[M+H]⁺＝960.3。

Example 8.13: synthesis of (2S,3S) -2- (((allyloxy) carbonyl) amino) -3- (tert-butoxy) butanoic acid (intermediate O)

To a round bottom flask containing O-tert-butyl-L-allo-threonine (2.3g, 13.13mmol) in NaOH (26.9mL, 26.9mmol) and cooled in an ice bath was added allyl chloroformate (1.54mL, 14.44mmol) in dioxane (15mL) dropwise through an addition funnel. Additional 1N NaOH was then added until the pH was about 9-10. The resulting mixture was warmed to room temperature and stirred for 2 hours to complete the reaction. The reaction mixture was transferred to a separatory funnel and washed twice with ether. The aqueous phase was collected, acidified to pH about 2, and extracted twice with EtOAc. The combined organic phases were washed with brine, over Na ₂SO₄Drying, filtering, concentrating, and drying to obtain oilIntermediate O of (2) (int O) (3g, 88% yield).¹H NMR (400MHz, dichloromethane-d)₂) δ ppm1.16-1.35(m,12H)3.70(s,2H)3.98-4.09(m,1H)4.35(dd, J ═ 8.31,4.89Hz,1H)4.61(d, J ═ 5.38Hz,2H)5.25(dq, J ═ 10.51,1.39Hz,1H)5.30-5.56(m,1H)5.86-6.08(m,1H). the product was used in the next step without further purification.

Example 8.14: synthesis of N- (((9H-fluoren-9-yl) methoxy) carbonyl) -O- (difluoromethyl) -L-serine (intermediate P)

N- (tert-butoxycarbonyl) -O- (difluoromethyl) -L-serine (P-1)

The title compound was prepared as described in the literature examples described in patent US 2015/218212 a1,2015.

Step 1O- (difluoromethyl) -L-serine (P-2).

To a solution of P-1(1.56g, 6.11mmol) in dry DCM (vol.: 20mL) was added TFA (7.06mL, 92 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The obtained residue was diluted with toluene (10mL) and concentrated under reduced pressure. This procedure was repeated two more times to give P-2(0.948g, 100%) which was used in the next step without further purification. MS [ M + H ] ═ 156.0.

Step 2.N- (((9H-fluoren-9-yl) methoxy) carbonyl) -O- (difluoromethyl) -L-serine (intermediate P).

P-2(0.948g, 6.11mmol) was dissolved in a mixture of dioxane (40mL) and water (20mL) and cooled to 0 ℃. Sodium bicarbonate (30.8g, 36.7mmol) was added followed by Fmoc-Cl (1.739g, 6.72mmol) one minute later. The resulting mixture was stirred at 0 ℃ for 1 hour and then at room temperature overnight. EtOAc is added and the reaction mixture is taken up with H₂O, 1N HCl and brine washes. Passing the organic phase over Na₂SO₄Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 0-100% EtOAc/heptane) to afford Int P as a white solid after drying under high vacuum (1.6g, 4.24mmol, 69.4)％)。MS[M+H]＝378.1。

Example 8.14: synthesis of (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -L-alanine (DE1)

To a suspension of L-alanine (257mg, 2.88mmol) in MeOH (4mL) and water (0.4mL) at room temperature was added NaOH (115mg, 2.88 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then E1(1.02g, 2.74mmol) was added. The reaction mixture was cooled to-5 ℃ and stirred for 1 hour. Add NaBH in portions₄(42mg, 1.1mmol), maintaining the internal reaction temperature below 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by dropwise addition of water until gas evolution ceased, and concentrated under reduced pressure. The aqueous residue was extracted with EtOAc (2 × 50 mL). Loading the separated aqueous phase into

On the pad. With water, then 2M NH in water₄OH elutes the pad. The combined aqueous filtrates were lyophilized to give a white solid, which was then dissolved in water. The aqueous phase was acidified to pH 7 and used in CHCl₃20% IPA in (100mL) was extracted several times, diluted with brine, and taken up in CHCl₃Back-extracting with 20% IPA solution. The combined organic phases are passed over Na₂SO₄Dried, filtered and concentrated to give DE1(510mg, 42%) as a white solid, which was used in the next step without further purification. Analytical method 7: t is t_R＝0.49min；MS[M+H]⁺＝443.3。

The intermediates in table 12 below were prepared according to the procedure described in example 8.14 for DE 1.

Table 12:

example 8.15: synthesis of (S) -3- ((allyloxy) carbonyl) -2, 2-dimethyloxazolidine-4-carboxylic acid (intermediate E)

Step 1.(S) -2- (((allyloxy) carbonyl) amino) -3-hydroxypropionic acid (E-1)

To a round-bottomed flask containing L-serine (20.14g, 192mmol) was added NaOH (1M, 393mL, 393 mmol). The resulting mixture was cooled using an ice bath and allyl chloroformate (24.5mL, 230mmol) in dioxane (151mL) was added dropwise through the addition funnel. Additional NaOH (1M) was added until the pH was about pH 9-10. The reaction mixture was warmed to room temperature, stirred overnight, transferred to a separatory funnel, and extracted twice with ether. The aqueous phase was acidified to pH 2.5 and extracted three times with EtOAc. The combined organic phases are passed over Na ₂SO₄Drying, filtration and concentration gave 21g of the desired product. Additional product was recovered from the aqueous phase by adding brine and extracting twice with EtOAc. The combined organic phases are passed over Na₂SO₄Drying, filtration and concentration gave additional 6g E-1 (75%) which was used in the next step without purification.

Step 2.(S) -3- ((allyloxy) carbonyl) -2, 2-dimethyloxazolidine-4-carboxylic acid (intermediate E)

To a round bottom flask containing E-1(21g, 111mmol) in DCM (129mL) were added p-TsOH (2.11g, 11.10mmol) and dimethoxypropane (93g, 890 mmol). The resulting mixture was heated to reflux and stirred at reflux for 2 hours. The heat was removed and the reaction mixture was stirred at rt overnight, concentrated under reduced pressure and taken up in EtOAc. The organic phase was saturated with Na₂CO₃And (4) washing with an aqueous solution. The separated aqueous phase was acidified with 6N HCl to pH about 2. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with water and brine, over Na₂SO₄Drying, filtering and concentrating to obtain Int-E (6)g, 26.2 mmol). The product was used in the next step without purification.

Example 8.16: synthesis of (R) -tert-butyl 3- ((S) -2-amino-3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (intermediate F)

Step 1.(S) -allyl 4- (((R) -1- (tert-butoxycarbonyl) -3- (4-chlorobenzyl) piperidin-3-yl) carbamoyl) -2, 2-dimethyloxazolidine-3-carboxylate (F-1)

To a suspension of B2(4.96g, 15.27mmol) in DCM (100mL) were added DIPEA (6.38mL, 45.8mmol) and INT-E (3.5g, 15.27 mmol). The resulting mixture was cooled to 0 ℃ and HATU (6.39g, 16.80mmol) was added. The cooling bath was removed and the resulting solution was stirred at room temperature overnight, diluted with DCM (100mL) and washed with 5% NaHCO₃The aqueous solution and brine were washed twice. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel (eluting with 0-60% EtOAc in heptane) to give F-1 as a white foam (6.1g, 11.38mmol, 74.5%). Analysis method 5: t is t_R＝1.28min；MS[M+H]⁺＝536.3。

Step 2.(S) -allyl 4- (((R) -1- (tert-butoxycarbonyl) -3- (4-chlorobenzyl) piperidin-3-yl) (methyl) carbamoyl) -2, 2-dimethyloxazolidine-3-carboxylate (F-2)

To a solution of F-1(6.1g, 11.38mmol) in anhydrous DMF (50mL) under nitrogen at 0 deg.C was added NaH (1.00g, 25.03mmol) portionwise over 20 minutes. The resulting mixture was stirred at 0 ℃ for 2 h (becoming light brown) and MeI (2.85mL, 45.5mmol) was added and stirring continued at 0 ℃ for 6.5 h. Once LCMS showed complete consumption of starting material, the reaction mixture was taken up with saturated NaHCO ₃And (4) quenching the aqueous solution. The resulting yellow precipitate was collected by vacuum filtration and redissolved in EtOAc. The organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated to give F-2 as a yellow foam (6.37g, 11.58mmol, quant.). Analysis method 5: t is t_R＝1.12min；MS[M+H]⁺＝550.0。

Step 3.(R) -tert-butyl 3- ((S) -2- (((allyloxy) carbonyl) amino) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate, allyl ((S) -1- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) (methyl) amino) -3-hydroxy-1-oxoprop-2-yl) carbamate (F-3)

To a solution of F-2(1g, 1.818mmol) in DCM (25mL) was added 0.2M TFA dropwise in DCM (136mL, 27.3 mmol). After stirring at room temperature for 1 hour, additional DCM (100mL) was added and the resulting mixture was stirred overnight. The reaction mixture was quenched and saturated NaHCO₃And (4) washing with an aqueous solution. The organic phase was dried over sodium sulfate, filtered, and concentrated to about 50mL under reduced pressure.

To the above solution were added TEA (0.507mL, 3.64mmol) and (Boc)₂O (0.211mL, 0.909 mmol). The resulting mixture was stirred at room temperature for 1.5 h, diluted with 100mL EtOAc and diluted with 50mL saturated NaHCO₃And (4) washing with an aqueous solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (eluting with 0-100% EtOAc and hexanes) to give F-3 as a white foam (615mg, 1.206mmol, 66.3%). Analysis method 5: t is t _R＝1.13min；MS[M+H]⁺＝510.4。

Step 4.(R) -tert-butyl 3- ((S) -2- (((allyloxy) carbonyl) amino) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (F-4).

To a solution of F-3(615mg, 1.206mmol) in anhydrous ACN (10mL) was added Ag₂O (1397mg, 6.03mmol) and MeI (0.754mL, 12.06 mmol). The reaction was stirred overnight (16 hours) at room temperature under nitrogen in the dark. LCMS indicated the desired product was the major product. Passing the reaction mixture through

The pad was filtered and the filtrate was concentrated under reduced pressure to give F-4(591mg, 1.128mmol, 94%) as a white foam. Analysis method 5: t is t_R＝1.23min；MS[M+H]⁺＝524.0。

Step 5.(R) -tert-butyl 3- ((S) -2-amino-3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (intermediate F).

To a solution of F-4(591mg, 1.128mmol) and N, N,1,1, 1-pentamethylsilylamine (793mg, 6.77mmol) in DCM (20mL) was added tetrakis (triphenylphosphine) palladium (0) (65.2mg, 0.056mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness. The resulting oil Int-F was used in the next step without further purification. Analysis method 5: t is t_R＝1.07min；MS[M+H]⁺＝440.2。

Example 8.17: synthesis of (R) -tert-butyl 3- ((S) -2-amino-3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (intermediate G)

To a flask containing F-2(2.1g, 3.82mmol) and N, N-dimethyltrimethylsilylamine (2.69g, 22.91mmol) was added DCM (10mL) followed by Pd (PPh)₃)₄(0.221g, 0.191 mmol). The mixture obtained is treated with N₂Bubbling for 5 minutes, then at room temperature under N₂Stirred under atmosphere for 90 minutes. Water (0.2mL) was added and the reaction mixture was concentrated under reduced pressure to afford the desired product, Int G, as the major product by LC/MS. This material was used in the next step without purification.

Alternatively, Int-G can be prepared as shown in the following scheme, starting from B2, as shown below.

Step 1.(S) -benzyl 4- (((R) -1- (tert-butoxycarbonyl) -3- (4-chlorobenzyl) piperidin-3-yl) carbamoyl) -2, 2-dimethyloxazolidine-3-carboxylate (G-1)

To a solution of intermediate B2(524mg, 1.613mmol) in anhydrous ACN (5mL) was added DIPEA (0.563mL, 3.23mmol) and (S) -3- ((benzyloxy) carbonyl) -2, 2-dimethyloxazolidine-4-carboxylic acid (496mg, 1.774mmol) followed by HATU (675mg, 1mmol)774 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated. The crude material was purified by silica gel ISCO flash column chromatography eluting with 0-50% EtOAc in heptane to give G-1 as a white foam (817mg, 1.394mmol, 86%). Analysis method 5: t is t _R＝1.34min；MS[M+H]⁺-100 ═ 486.3.TLC: Rf ═ 0.53; 1:1 EtOAc/heptane.

Step 2 benzyl 4- (((R) -1- (tert-butoxycarbonyl) -3- (4-chlorobenzyl) piperidin-3-yl) (methyl) carbamoyl) -2, 2-dimethyloxazolidine-3-carboxylate (G-2).

To a solution of G-1(560mg, 0.955mmol) in anhydrous DMF (15mL) under nitrogen at 0 deg.C was added 60% (in mineral oil) NaH (76mg, 1.911 mmol). The resulting mixture was stirred at 0 ℃ for 30 min, and MeI (0.179mL, 2.87mmol) was added. The reaction mixture was stirred at 0 ℃ for 60 minutes. LCMS showed starting material still present. An additional 1.0 equivalent of NaH was added and stirring was continued for an additional 30 minutes. Additional MeI was added and the reaction mixture was stirred for an additional 30 minutes, then saturated NaHCO₃Aqueous solution and water quench. The resulting white precipitate was collected by vacuum filtration and redissolved in EtOAc. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give G-2(500mg, 0.833mmol, 87%), which was used in the next step without further purification. Analysis method 5: t is t_R＝1.36min；MS[M+H]⁺＝600.4。

Step 3 (3R) -tert-butyl 3- (2-amino-3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (Int-G).

To a mixture of G-2(660mg, 1.100mmol) in EtOH (100mL) under nitrogen was added Pd-fibroin (731mg, 0.110 mmol). The resulting mixture was fitted with a hydrogen balloon and stirred at room temperature for 5 hours. An additional 731mg of Pd-fibroin was added, and the reaction mixture was stirred overnight. The hydrogen balloon was disconnected and the reaction flask was flushed with nitrogen three times before exposure to air. By prewetting with DCM

The reaction mixture was filtered through a pad and washed with additional DCM. The filtrate was concentrated under reduced pressure to give a crude product which was purified by reverse phase column chromatography (using a column containing 0.1% NH)₄0-100% ACN water elution of OH) to give Int-G (57mg, 0.134mmol, 12.2%). Analysis method 5: t is t_R＝0.97min；MS[M+H]⁺＝426.4。

Example 8.18: synthesis of N- (tert-butoxycarbonyl) -N- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -L-alanine (intermediate H)

To a slurry of DE2(12.85g, 27.9mmol) in ACN (232mL) was added tetramethylammonium hydroxide pentahydrate (2.54g, 27.9mmol) at room temperature. The resulting slurry was stirred for 20 min and Boc anhydride (9.13g, 41.8mmol) was added. The reaction mixture was stirred overnight, then quenched with water and concentrated under reduced pressure to remove excess ACN. The pH of the resulting aqueous phase was adjusted to about pH 5.5 with 1N HCl and extracted twice with 2-methyltetrahydrofuran. The organic phases were combined, dried over sodium sulfate, filtered, concentrated and dried under high vacuum to give Int-H (12.92g, 83%).

Example 8.19: synthesis of tert-butyl (S) -3- ((R) -3- ((S) -2- ((S) -2-aminopropionamide) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluorovalerate (intermediate K)

Step 1. Tert-butyl (R) -3- ((S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (K-1)

To a solution of Fmoc-Ser (OMe) -OH (2.84g, 8.31mmol, 1.08 equiv.) in DMF (25mL) was added HATU (3.16g, 8.31mmol, 1.08 equiv.) and DIPEA (2.69mL, 15.39 mmol). The resulting mixture was stirred for 2 minutes, then a solution of B2(2.5g, 7.70mmol) in DMF (10mL) was added in one portion. Mixing the reactionThe material was stirred at rt and then diluted with EtOAc. The organic phase was washed with 5% NaHCO₃Washed twice with aqueous solution and brine, over Na₂SO₄Drying, filtration and concentration gave K-1(5.66g) as a pale yellow foam, which was used in the next step without further purification. Analytical method 7: t is t_R＝1.39min；MS[M+Na]⁺＝670.2。

Step 2. tert-butyl (R) -3- ((S) -2-amino-3-methoxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (K-2)

To a solution of K-1(5.66g, 7.68mmol) in DMF (40mL) was added 4-methylpiperidine (10mL, 85 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness. The residue was diluted with EtOAc. The organic phase is treated with H₂Washed with brine, Na₂SO₄Drying, filtration and concentration gave K-2(6.42g) as a pale yellow solid which was used in the next step without further purification. Analysis method 5: t is t _R＝1.09min；MS[M+H]⁺＝426.3。

Step 3. tert-butyl (R) -3- ((S) -2- ((S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propanamide) -3-methoxypropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (K-3)

To a solution of Fmoc-Ala-OH (4.79g, 15.37mmol) in DMF (45mL) was added HATU (5.85g, 15.37mmol) and DIPEA (6mL, 34.4 mmol). The resulting mixture was stirred for 2 minutes, then a solution of K-2(6.42g, 7.69mmol) in DMF (15mL) was added in one portion. The reaction mixture was stirred at rt and then diluted with EtOAc. The organic phase was washed with 5% NaHCO₃Washed twice with aqueous solution and brine, over Na₂SO₄Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 0-100% EtOAc/heptane) to afford K-3(1.69g, 30.6%) as a yellow foam. Analysis method 5: t is t_R＝1.34min；MS[M+H]⁺＝719.5。

Step 4. (9H-fluoren-9-yl) methyl ((S) -1- (((S) -1- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) amino) -3-methoxy-1-oxoprop-2-yl) amino) -1-oxoprop-2-yl) carbamate (K-4)

To a solution of K-3(1.69g, 2.35mmol) in DCM (5mL)HCl in dioxane (12mL, 48.0mmol) was added dropwise to the solution. The resulting mixture was stirred at room temperature for 1 hour and then concentrated to give K-4(1.8g) as a yellow foam, which was used in the next step without further purification. Analysis method 5: t is t _R＝1.18min；MS[M+H]⁺＝619.3。

Steps 5 and 6. Tert-butyl (S) -3- ((R) -3- ((S) -2- ((S) -2-aminopropionamide) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-Trifluorovalerate (intermediate K)

To a solution of A14(0.72g, 2.81mmol, 1.2 equiv.) in DMF (10mL) was added HATU (1.077g, 2.83mmol) and DIPEA (2.06mL, 11.81 mmol). The resulting mixture was stirred for 2 minutes, then a solution of K-4(1.8g, 2.36mmol) in DMF (5mL) was taken in one portion. The reaction mixture was stirred at room temperature for 1 hour, then 4-methylpiperidine (4.5mL, 38.1mmol, 16 equivalents) was added in one portion. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness. Subjecting the crude product to reverse phase column chromatography (with 0-100% ACN/H)₂O (with 0.1% NH)₄OH) elution) to yield Int-K as an off-white foam. Analysis method 4: t is t_R＝1.88min；MS[M+H]⁺＝635.4。

Example 8.20: synthesis of (R) -methyl 4- ((R) -3- ((S) -3- ((S) -2-aminopropionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutyrate trifluoroacetate (intermediate M)

Step 1.(R) -tert-butyl 4- ((R) -3-amino-3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutyrate (M-1)

DIPEA (0.323mL, 1.848mmol) and HATU (358mg, 0.942mmol) were added in portions to a vial containing C3(244mg, 0.924mmol) in DMA (4mL) at room temperature. Once addition was complete, the resulting mixture was stirred at room temperature for an additional 15 minutes and then added dropwise to another vial containing B7(275mg, 0.924mmol) in DMA (1.5mL) and DIPEA (0.807mL, 4.62 mmol). The reaction mixture was stirred at rt overnight, then transferred to a separatory funnel, diluted with EtOAc, and washed with saturated aqueous sodium bicarbonate and brine (x 3). The organic phase was dried over sodium sulfate, filtered and concentrated to give M-1(435mg, quantitative yield), which was used in the next step without purification.

Step 2.(R) -methyl 4- ((R) -3-amino-3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutyrate (M-2)

To a round-bottomed flask containing M-1(435mg, 0.924mmol) in anhydrous methanol (18mL) and cooled in an ice bath was added thionyl chloride (1.35mL, 18.47mmol) dropwise. When the addition was complete, the resulting mixture was gradually warmed to room temperature and then stirred overnight to complete the reaction. The reaction mixture was concentrated to dryness under reduced pressure under heating in a 30 ℃ water bath. The crude oil was dissolved in EtOAc, washed with half-saturated aqueous sodium bicarbonate solution, then brine. The separated organic phase was dried over sodium sulfate, filtered and concentrated to give M-2(408mg, quantitative yield), which was used in the next step without purification.

Step 3.(R) -methyl 4- ((R) -3- ((S) -3- ((S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutyrate (M3)

To a vial containing M-2(408mg, 0.951mmol) and (S) -3- ((S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propanoyl) -2, 2-dimethyloxazolidine-4-carboxylic acid (417mg, 0.951mg) was added DMA (4.7mL) and DIPEA (0.249mL, 1.427mmol) with stirring. HATU (362mg, 0.951mmol) was then added in one portion, and the resulting mixture was stirred at room temperature overnight to complete the reaction. EtOAc was added and the reaction mixture was transferred to a separatory funnel and washed with half-saturated sodium bicarbonate solution. The organic phase was washed three times with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 0-55% DCM/EtOAc) to afford M-3(660mg, 82%) after concentration of the pure fraction under reduced pressure.

Step 4.(R) -methyl 4- ((R) -3- ((S) -3- ((S) -2-aminopropionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutyrate trifluoroacetate (intermediate M)

To a round bottom flask containing M-3(660mg, 0.777mmol) in DMF (5mL) at room temperature was added 4-methylpiperidine (2.75mL, 23.31mmol) and the resulting mixture was stirred for 35 minutes. The resulting white slurry was cooled in an ice bath and quenched dropwise with acetic acid (1.56mL, 27.2 mmol). Water (0.5mL) was then added and the slurry was filtered and the filtrate was purified by C18 column reverse phase column chromatography with three injections (elution with 30-70% water/ACN, 0.1% TFA). After freeze-drying, the pure fraction gave Int M as a white powder (576mg, quantitative yield)

The intermediates in table 13 below were prepared according to the procedure described for intermediate M in 8.20.

Table 13:

example 8.21: synthesis of (3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 83)

(R) -tert-butyl 3- ((S) -3- ((S) -2-aminopropionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (1-2)

To a solution of B2(2.5g, 7.70mmol) and Fmoc-Ala-Ser [ psi (Me, Me) pro ] -OH (3.64g, 8.31mmol) in DMF (30.8ml) was added DIEA (2.69ml, 15.39mmol) followed by HATU (3.16g, 8.31mmol) as a solid in one portion. The resulting clear yellow mixture was stirred overnight.

To the reaction mixture containing the desired intermediate 1-1 was added 4-methylpiperidine (3.63ml, 30.8mmol) and stirring was continued at room temperature for 3 hours. Methanol was added and the reaction mixture was concentrated under reduced pressure (at 50 ℃) to remove DMF. The solid obtained was then taken up in a large amount of EtOAc and washed twice with half-saturated sodium bicarbonate solution and brine. The combined organic phases were dried over sodium sulfate, filtered and concentrated to give 1-2 as a white solid (3.5g, about 90% yield; containing some Fmoc adduct), which was used in the next step without purification. Analytical method 5, t_R＝1.07min.,[M+H]⁺＝523.2。

Step 3.(R) -tert-butyl 3- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (1-3)

To a round bottom flask containing 1-2(3.5g, 6.69mmol) and E1(2.72g, 7.36mmol) dissolved in DCM (268ml) was added acetic acid (1.532ml, 26.8 mmol). The resulting mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (7.09g, 33.5mmol) was added as a solid in two portions. The reaction mixture was stirred at room temperature overnight and then concentrated. The obtained residue was diluted with EtOAc and water. The organic phase was washed with saturated NaHCO ₃Washed twice with brine and over Na₂SO₄Dried, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with 0-10% DCM/MeOH) to give 1-3 as an off-white solid (4.4g, 5.02mmol, 75.0% yield). Analytical method 5, t_R＝1.33min.,[M+H]⁺＝876.2

Step 4.(S) -3- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionyl) -N- ((R) -3- (4-chlorobenzyl) piperidin-3-yl) -2, 2-dimethyloxazolidine-4-carboxamide (1-4)

To a round bottom flask containing ACN (60mL) cooled in an ice bath and 1-3(4.4g, 5.02mmol) in water (5mL) was added TFA (30.9mL, 401mmol) dropwise over two minutes. The ice bath was removed and stirring was continued at room temperature for 45 minutes. Additional TFA (about 10mL) was added and the reaction mixture was stirred at room temperature for 2.5 hours, then concentrated under reduced pressure to remove most of the solvent. The residue obtained is carefully treated with saturated sodium bicarbonate solution and then with NaOH (1N) with stirring until the pH of the aqueous solution is 8. Mixing the obtained extractsThe compound was extracted twice with EtOAc and the combined organic phases were washed with brine, then dried over sodium sulfate, filtered and concentrated to afford 1-4 as an off-white foam (2.5g, 3.22mmol, 64.1% yield). This material was used in the next step without purification. Analytical method 5, t _R＝1.17min.,[M+H]⁺＝776.1

Step 5. tert-butyl (S) -3- ((R) -3- ((S) -3- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluorovalerate (1-5)

To a solution of A14(120mg, 0.468mmol) in DMF (2mL) was added DIPEA (0.20mL, 1.16mmol) and HATU (184mg, 0.483 mmol). The resulting mixture was stirred at room temperature for 5 minutes, then added to a solution of 1-4(300mg, 0.386mmol) in DMF (2 mL). The reaction mixture was stirred for a further 1 hour and then with 5% NaHCO₃The solution was quenched and extracted with EtOAc. The organic phase was washed with 5% NaHCO₃The solution and brine were washed, dried over sodium sulfate, filtered and concentrated to give 1-5(450mg) as a brown oil. The crude product was used directly in the next step without further purification. Analytical method 5, t_R＝1.37min.,[M+H]⁺＝1014.3。

Step 6.(S) -3- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionamide) -3-hydroxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (1-6)

To a solution of 1-5(450mg, 0.443mmol) in DCM (3mL) was added TFA (3mL, 38.9mmol) dropwise at 0 deg.C. The resulting mixture was stirred at room temperature for 2 hours, then H was added ₂O (3mL) and ACN (3mL) and stirring was continued for another 1-2 hours. The reaction mixture was concentrated, diluted with DCM and saturated NaHCO₃/Na₂CO₃The aqueous solution was adjusted to pH 7-8. The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give 1-6 as a pale yellow oil (289mg, 71% yield), which was used in the next step without further purification. Analytical method 5, t_R＝0.83min.,[M+H]⁺＝918.1。

Step 7.(S) -3- ((R) -3- ((S) -3- ((tert-butyldimethylsilyl) oxy) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (1-7)

To a solution of 1-6(289mg, 0.315mmol) in DCM (10mL) was added imidazole (139mg, 2.042mmol) and TBSCl (233mg, 1.546 mmol). The resulting mixture was stirred at room temperature for 3 hours, and then washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated. Subjecting the crude product to basic reverse phase column chromatography (with 5-100% water/ACN (containing 0.1% NH)₄OH) elution) and the pure fractions were lyophilized to give 1-7(132mg, 40.6%) as a white solid. Analytical method 5, t_R＝1.10min.,[M+H]⁺＝1032.3。

Step 8.(3S,7S,10S,13R) -10- (((tert-butyldimethylsilyl) oxy) methyl) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (1-8)

To a solution of 1-7(132mg, 0.128mmol) in DCM (100mL) were added HOAt (17.39mg, 0.128mmol), HATU (194mg, 0.511mmol) and 2, 6-dimethylpyridine (0.35mL, 3.01 mmol). The resulting mixture was refluxed at 48 ℃ overnight and then concentrated to dryness. The residue obtained was taken up in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic phase was washed with brine, over Na₂SO₄Drying, filtration and concentration gave 1-8(200mg, crude) as a brown oil. The crude product was used directly in the next step without further purification. Analytical method 5, t_R＝1.49min.,[M+H]⁺＝1014.4。

Step 9.(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 83)

To 1-8(200mg, 0.197mmol) in DCM (2mL)To the solution was added TFA (2mL, 26.0mmol) dropwise. The resulting mixture was stirred at room temperature for 1 hour, then concentrated to dryness. The residue was dissolved in DCM and saturated NaHCO₃And (4) washing with an aqueous solution. The organic phase was separated and concentrated to dryness. Subjecting the crude product to reverse phase column chromatography (with 10-100% water/ACN (containing 0.1% NH) ₄OH) elution) and freeze dried the pure fractions to give compound 83 as a white solid (46mg, 25%). Analytical method 3, t_R＝1.06min.[M+H]⁺＝900.3。

The compounds in table 14 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 83 in example 8.21.

Table 14:

example 8.22: synthesis of (3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 82)

Step 1.(R) -tert-butyl 3- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (2-1)

To a solution of Int G (1.003G, 2.12mmol) and DE2(0.977G, 2.120mmol) in DMF (10mL) was added DIPEA (1.481mL, 8.48mmol) and the resulting mixture was stirred at room temperature for 5 min. TBTU (0.681g, 2.120mmol) was added thereto and the mixture was cooled in a chamberStirring was continued at room temperature for 16 hours. The reaction mixture was washed with EtOAc (200mL) and 5% NaHCO ₃The aqueous solution (15mL) was partitioned. The organic phase was washed with 5% NaHCO₃(3X10mL) and brine (10mL) over Na₂SO₄Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 0-15% DCM/MeOH with 0.2TEA modifier to give 2-1 as a pale yellow solid (1.20g, 1.312mmol, 61.9% yield). Analytical method 5, t_R＝1.30min,[M+H]⁺＝868.6。

Step 2.(S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -N- ((R) -3- (4-chlorobenzyl) piperidin-3-yl) -3-hydroxy-N-methylpropanamide (2-2)

To a solution of 2-1(300mg, 0.345mmol) in dioxane (4ml) was added dropwise HCl in dioxane (4N, 1.73ml, 6.91mmol) at 0 ℃. The resulting mixture was heated and stirred at room temperature overnight to give a white slurry. The reaction mixture was concentrated and dried under high vacuum to give 2-2 as an off-white solid. This material was used in the next step without purification (303mg, quantitative yield). Analytical method 5, t_R＝1.13min,[M+H]⁺＝768.5。

Step 3.(S) -tert-butyl 3- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluorovalerate (2-3)

To a solution of 2-2(303mg, 0.328mmol) and a14(88mg, 0.344mmol) in DMF (3mL) was added DIPEA (0.23mL, 1.31mmol) and the resulting mixture was stirred at room temperature for 5 min to ensure all solids were dissolved. HATU (131mg, 0.344mmol) was added and stirring continued at room temperature for 16 h. The reaction mixture was taken up in EtOAc and washed with saturated NaHCO₃The solution and brine washes. Passing the organic phase over Na₂SO₄Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 0-15% DCM/MeOH (with 1% TEA) to give 2-3(220mg, 0.208mmol, 63.3% yield) after concentration of the pure fractions. Analysis methodMethod 5, t_R＝1.32min,MS[M+H]⁺＝1006.7。

Step 4.(S) -3- ((R) -3- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (2-4)

To a solution of 2-3(220mg, 0.218mmol) in DCM (10mL) was added TFA (1mL, 12.98mmol) at 0 deg.C, and the resulting mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was concentrated to dryness under reduced pressure and dried under high vacuum. The crude product was purified by reverse phase column chromatography (with 10-80% water/ACN (with 0.1% NH) ₄OH) elution) to yield the desired product. The fractions were collected and concentrated in vacuo to remove ACN and give a residue that was predominantly aqueous, which was then extracted with DCM (x 4). The organic phase is passed over MgSO₄Drying, filtration, and concentration in vacuo afforded 2-4(132mg, 0.139mmol, 63.5% yield) as a white solid. Analytical method 5, t_R＝0.85min,[M+H]⁺＝950.6。

Step 5.(S) -3- ((R) -3- ((S) -3- ((tert-butyldimethylsilyl) oxy) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (2-5)

TBSCl (62.8mg, 0.416mmol) was added dropwise to a solution of 2-4(132mg, 0.139mmol) and imidazole (28.4mg, 0.416mmol) in DCM (15mL) at 0 deg.C. The resulting mixture was warmed to room temperature and stirred overnight. Additional TBSCl (630mg) and imidazole (280mg) were added and stirring was continued for 5 h. The reaction mixture was quenched with water (100ml) and the organic phase was collected, dried over sodium sulfate, filtered and concentrated. The crude product was purified by basic reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH) elution) and freeze-drying the fractions containing the pure product gave 2-5(95mg, 0.085mmol, 61.0% yield). Analytical method 5, t _R＝1.43min,[M+H]⁺＝1064.4。

Step 6.(3S,7S,10S,13R) -10- (((tert-butyldimethylsilyl) oxy) methyl) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (2-6)

To a solution of 2-5(95mg, 0.09mmol) in DCM (100mL) were added 2, 6-lutidine (0.21mL, 1.78mmol), HOAt (12.1mg, 0.09mmol) and HATU (136mg, 0.36mmol) and the resulting mixture was heated in a heating bath at 40 ℃ for 16 h. The reaction mixture was cooled to room temperature and quenched with NaHCO₃And a brine wash. Passing the organic phase over Na₂SO₄Dried, filtered and concentrated to give 2-6 as a crude oil (142 mg). This material was used in the next step without purification. Analytical method 5, t_R＝1.56min,[M+H]⁺＝1046.4。

Step 7.(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (compound 82)

To a solution of 2-6(142mg, 0.136mmol) in DCM (vol.: 2mL) was added TFA (2mL, 26.0mmol) dropwise at 0 deg.C, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue was taken up in DCM. The organic phase was washed with saturated NaHCO ₃The solution was washed, filtered and concentrated. The crude product was purified by reverse phase column chromatography (with 10-100% water/ACN (with 0.1% NH)₄OH) elution) and freeze drying to obtain the required product. The material was then purified again using basic HPLC, and the pure fractions were collected and lyophilized to give compound 82 as a white solid (20mg, 0.021mmol, 15.49% yield). Analytical method 7, t_R＝0.93min.,[M+H]⁺＝932.2。

The compounds in table 15 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 82 in example 8.22.

Table 15:

example 8.23: synthesis of (3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 22)

Step 1.(R) -tert-butyl 3- ((S) -2- ((S) -2- ((tert-butoxycarbonyl) (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (3-1)

To a solution of Int H (0.80g, 1.45mmol) and intermediate F (0.86g, 1.46mmol) in ACN (20mL) were added DIPEA (0.51mL, 2.89mmol) and HATU (0.58g, 1.52mmol), and the resulting mixture was stirred at room temperature for 0.5H. The reaction mixture was taken up with 20mL of saturated NaHCO ₃And 20mL of water and extracted with EtOAc. The organic phase was washed with 5% NaHCO₃The solution was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 0-15% DCM/MeOH with 0.2% TEA to give 3-1 as a yellow foam after concentration of the pure fractions (1.36g, 86% yield). Analytical method 5, t_R＝1.47min,[M+H]⁺＝982.8。

Step 2: (S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -N- ((R) -3- (4-chlorobenzyl) piperidin-3-yl) -3-methoxy-N-methylpropanamide (3-2)

To a solution of 3-1(1.36g, 1.25mmol) in anhydrous dioxane (6mL) and cooled in an ice bath was added cold HCl in dioxane (4N, 6mL, 24.0 mmol). The cooling bath was removed and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give a crude residue, which was taken up in toluene and concentrated again (repeat) to give 3-2 as a yellow solid (1.23g, ca. quantitative yield). The material was used in the next step without further purification. Analytical method 5, t_R＝1.27min,[M+H]⁺＝782.5。

Step 3 (S) -tert-butyl 3- ((R) -3- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluorovalerate (3-3)

To a solution of 3-2(0.71g, 0.80mmol) in 10mL ACN was added DIPEA (0.56mL, 3.18mmol) and A14(0.20g, 0.80mmol), followed by HATU (0.30g, 0.80 mmol). The resulting mixture was stirred for 1 hour with 20ml of 5% NaHCO₃Quenched and extracted with EtOAc. The combined organic phases were washed with 5% NaHCO₃Washed with brine, dried over sodium sulfate, filtered and concentrated to give 3-3 as a yellow solid (550mg, 61% yield). The material was used in the next step without further purification. Analytical method 4, t_R＝1.79min,[M+H]⁺＝1020.6。

Step 4: (S) -3- ((R) -3- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (3-4)

To a solution of 3-3(550mg, 0.46mmol) in DCM (3mL) at 0 deg.C was added TFA (5mL, 64.9 mmol). The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo (toluene was added as an azeotrope to aid TFA removal) and the crude product was purified by reverse phase column chromatography (with 0-50% water/ACN (with 0.1% NH)₄OH) elution) pureConversion and lyophilization gave 3-4 as a white fluffy powder (138mg, 30% yield). Analytical method 5, t _R＝0.85min,[M+H]⁺＝964.6。

Step 5 (3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (example 22)

To a solution of 3-4(138mg, 0.14mmol) in anhydrous DCM (100mL) were added 2, 6-lutidine (0.25mL, 2.10mmol), HOAt (20.0mg, 0.14mmol), and HATU (277mg, 0.56 mmol). The resulting mixture was refluxed overnight at 48 ℃ using a heating bath. The reaction mixture was then concentrated to dryness in vacuo and concentrated in EtOAc (100mL) and 5% NaHCO₃The aqueous solution (30mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 30mL) and brine (30mL) were washed over Na₂SO₄Dried, filtered and concentrated. The crude oil was diluted with ACN and purified by ISCO on a 100g C18 chromatography column eluting with 0-100% ACN in water (0.1% TFA as modifier) to afford compound 22 as a white solid after lyophilization (76mg, 56% yield). Analytical method 3, t_R＝1.13min.,[M+H]⁺＝946.35。

The compounds in table 16 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 22 in example 8.23.

Table 16:

example 8.24: synthesis of (3S,7S,10S,13R) -6- (2- (4- (2- (azetidin-1-ylmethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 33)

Step 1.(S) -tert-butyl 3- ((R) -3- ((S) -2- ((S) -2- ((2- (4- (2- (azetidin-1-ylmethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) amino) propanamide) -3-methoxypropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoate (4-1)

To a solution of intermediate K (250mg, 0.39mmol) and E12(150mg, 0.39mmol) in DCM (20mL) was added acetic acid (0.09mL, 1.58mmol) at room temperature and the resulting mixture was stirred for 1 hour. Sodium triacetoxyborohydride (417mg, 1.97mmol) was added in one portion and stirring was continued at room temperature overnight. The reaction mixture was quenched with methanol and concentrated under reduced pressure. The resulting residue was taken up in EtOAc and washed twice with half-saturated sodium carbonate solution and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. Flash column chromatography on silica gel (eluting with 0-20% MeOH in DCM) gave 4-1(293mg, 74% yield) after concentration of the pure fractions. MS [ M + H ] ]⁺＝1000.5

Step 2.(S) -3- ((R) -3- ((S) -2- ((S) -2- ((2- (4- (2- (azetidin-1-ylmethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) amino) propionamide) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (4-2)

To a solution of 4-1(293mg, 0.29mmol) in DCM (2.5mL) and cooled in an ice bath was added trifluoroacetic acid (2mL, 26.1mmol) dropwise. The resulting mixture was gradually warmed to room temperature and stirred for 40 minutes. The reaction mixture was cooled in an ice bath and then quenched by dropwise addition of a cooled saturated sodium bicarbonate solution (26 mL). Additional DCM was added and the mixture was gradually warmed to room temperature and stirring was continued for 1 hour. The biphasic mixture was passed through a phase separator and the organic phase was dried over sodium sulfate, filtered and concentrated to give 4-2 as crude product (277mg, assuming quantitative yield). The crude material was used directly in the next step without purification. MS [ M + H ]]⁺＝944.6

Step 3.(3S,7S,10S,13R) -6- (2- (4- (2- (azetidin-1-ylmethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 33)

To a solution of 4-2(277mg, 0.29mmol) in anhydrous DCM (250mL) were added 2, 6-lutidine (1.02mL, 8.79mmol), HOAt (40mg, 0.29mmol), and HATU (446mg, 1.173 mmol). The resulting mixture was heated to 45 ℃ overnight. The reaction mixture was cooled and filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue obtained is taken up in DCM and the organic phase is washed with half-saturated sodium bicarbonate solution. The organic phase was then dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 0-20% MeOH in DCM, the product eluting at about 15% MeOH) to afford the desired product after concentration of the pure fractions. The product was taken up in 1:1 ACN/water and lyophilized to give compound 33 as a white powder. Analytical method 3, t_R＝1.12min.,[M+H]⁺＝926.3。

The compounds in table 17 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 33 in example 8.24.

Table 17:

example 8.25: synthesis of (3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 50)

Step 1.(R) -methyl 3-benzyl-4- ((R) -3- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutyrate (5-1)

The title compound 5-1 was prepared according to the procedure described for example 8, step 1, starting from Int M (200mg, 0.27mmol) and E1(100mg, 0.27 mmol). After work-up and purification, the product 5-1 was obtained (213mg, 72% yield). MS [ M + H ]]⁺＝982.8。

Step 2.(R) -3-benzyl-4- ((R) -3- ((S) -3- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutanoic acid (5-2)

To a round bottom flask containing 5-1(213mg, 0.22mmol) in dioxane (10mL) and water (2.5mL) was added sodium hydroxide (1M, 0.87mL, 0.87mmol) dropwise. The resulting mixture was stirred at room temperature for 2 hours, cooled in an ice bath and quenched with HCl (1M, 0.65mL, 0.65mmol) in water (1.4mL), the reaction mixture was warmed to room temperature, stirred for 15 minutes and then lyophilized to give example 5-2 as an off-white powder (210mg, quantitative). This material was used in the next step without purification. MS [ M + H ] ]⁺＝965.8。

Step 3.(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 50)

To a solution of 5-2(210mg, 0.22mmol) in anhydrous DCM (210mL) were added 2, 6-lutidine (0.76mL, 6.52mmol), HOAt (30mg, 0.22mmol), and HATU (330mg, 0.87 mmol). The resulting mixture was heated to 45 ℃ overnight. The resulting cloudy mixture was cooled and filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was taken up in DCM and washed with half-saturated sodium bicarbonate solution. The organic phase was then dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 0-20% MeOH in DCM, the product eluting at about 10% MeOH) to give the cyclized intermediate (142mg, 69% yield) which was used directly in the next step. MS [ M + H ]]⁺＝948.5。

To a vial containing cyclized intermediate (142mg, 0.15mmol) in ACN (5mL) and water (3mL) and cooled in an ice bath was added trifluoroacetic acid (1.44mL, 18.70mmol) dropwise. The resulting mixture was warmed to room temperature and stirred for about 1 hour. The reaction mixture was then diluted with a 1:1 mixture of ACN/water and freeze-dried. The crude solid was taken up in EtOAc, half-saturated sodium bicarbonate solution was added and the resulting mixture was stirred vigorously for 15 minutes to give a biphasic mixture. The aqueous phase was drained off and the organic phase was washed with saturated aqueous sodium bicarbonate solution (x2) and brine (x2), dried over sodium sulfate, filtered and concentrated. The crude residue was taken up in 1:1 ACN/water and lyophilized to give compound 50 as a white powder (123mg, 86% yield). Analytical method 3, t _R＝1.07min.,[M+H]⁺＝908.4

The compounds in table 18 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 50 in example 8.25.

Table 18:

example 8.26: synthesis of (3S,7S,10S,13R) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -6- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 55)

Step 1.(S) -tert-butyl 4- ((R) -3-amino-3- (4-chlorobenzyl) piperidin-1-yl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutyrate (6-1)

To a solution of A4(1.376g, 4.74mmol) and TBTU (1.522g, 4.74mmol) in DMA (10mL) was added DIEA (1.08mL, 6.16 mmol). The resulting mixture was stirred at room temperature for 5 minutes, then added to a solution of B7(1.41g, 4.74mmol) in DMA (10mL) and DIEA (3.31mL, 18.96 mmol). The reaction mixture was stirred at room temperature for 2.5 h, the solvent was removed in vacuo, and the resulting residue was taken up in EtOAc (100mL) and 1M NaHCO₃The aqueous solution (40mL) was partitioned. The organic phase is washed with 1M NaHCO₃(2X15mL) and brine (15mL) over Na₂SO₄Drying, filtration, and concentration to dryness gave 6-1 as a yellow solid (2.4g, 3.86mmol, 81% yield). The product was used in the next step without purification. Analytical method 5, t _R＝1.30min.,[M+H]⁺＝497.4。

Step 2.(S) -tert-butyl 4- ((R) -3- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutyrate (6-2)

To 6-1(2.4g, 4.83mmol) in DCM (20mL) was added a solution of DIPEA (1.69mL, 9.66mmol) and Fmoc-Cl (1.25g, 4.83mmol) in DCM (10mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was taken up in EtOAc (70mL) and 1M NaHCO₃(50 mL). The organic phase is washed with 1M NaHCO₃Washed (50mL), water (100mL) and brine (100mL) over Na₂SO₄Dried, filtered and concentrated to dryness. The crude product was purified by flash column chromatography on silica gel (eluting with 0-40% EtOAc/heptane) to give 6-2 as a white foam after concentration of the pure fractions (2.2g, 2.91mmol, 60.2% yield). Analysis methodMethod 5, t_R＝1.56min.,[M+H]⁺＝718.7。

Step 3 (S) -4- ((R) -3- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid (6-3)

To a solution of 6-2(2.2g, 3.06mmol) and lutidine (3.56mL, 30.6mmol) in DCM (50mL) was added trimethylsilyl triflate (2.76mL, 15.29mmol) dropwise at 0 deg.C. The resulting mixture was stirred at 0 ℃ for 3 hours. DCM (100mL) and 5% KHSO were then added ₄Aqueous solution (50mL) and the phases were separated. Mixing the organic phase with 5% KHSO₄Aqueous (3 × 30mL) and brine (30mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness in vacuo gave 6-3 as an off-white solid (2.2g, 3.32mmol, quantitative yield). Analytical method 5, t_R＝0.92min.,[M+H]⁺The product was used in the next step without further purification.

Step 4 resin-loaded (S) -4- ((R) -3- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid (6-4)

Step 4-1: to 6-3(2.2g, 3.32mmol) dissolved in DCM (65mL) was added DIPEA (3.48mL, 19.90 mmol). The resulting mixture was added to a glass tube containing a prewashed 2-chlorotrityl chloride resin (6.22g, 9.95mmol) and shaken at room temperature for 16 hours. The reaction solution was drained and the resin washed with DCM (3X 40ml) and DMA (2X40 ml). Finally, the resin was taken up in a mixture of DCM/MeOH (50mL/20mL) and shaken for 30 min. The resulting mixture was drained and the resin was filtered and washed with DMF (2x40mL) and DCM (2x40 mL).

Step 4-2: to a glass tube containing the resin of step 4-1 was added a solution of 20% 4-Me-piperidine in DMF (100mL) and the resulting mixture was shaken at room temperature for 2 hours. The mixture was filtered, washed with DMF (100mL x2) and DCM (100mL x2) and dried under vacuum to give 6-4(6.3g, crude). A small amount of resin was cleaved with TFA to determine purity. Analytical method 7, t _R＝0.81min.,[M+H]⁺＝441.4。

Step 5 resin-loaded (S) -4- ((R) -3- ((S) -3- (((((9H-fluoren-9-yl) methoxy) carbonyl) -L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid (6-5)

Fmoc-Ala-Ser [ Psi-Pro ] was added to 6-4(4g, 8.79mmol) in a 40mL centrifuge tube]-a premixed solution of-OH (5.78g, 13.19mmol), DIPEA (6.14mL, 35.2mmol) and HATU (5.01g, 13.19mmol) in DMF (30mL) and the tube shaken at room temperature overnight. The resin was then filtered and washed with DMF (100mL x2) then DCM (100mL x2) to give 6-5(1.33g, crude). Analytical method 7, t_R＝1.33min；[M+H]⁺821.3 (unprotected serine quality).

Step 6 (S) -4- ((R) -3- ((S) -3- ((S) -2-aminopropionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid (6-6)

To 6-5(1.33g, 1.52mmol) in a 100mL glass tube was added 20% 4-Me-piperidine in DMF (50mL) and the tube was shaken at room temperature for 2 h. The resin was then filtered and washed with DMF (50mL x2) followed by DCM (50mL x 2). The resulting resin was placed back in a glass tube and a 20% solution of HFIP in DCM (50mL) was added. The mixture was shaken at room temperature for 20 minutes. And the solution was drained and collected. This procedure was repeated three times in total and the collected solution was concentrated in vacuo to give a crude solid. (about 1.6 g). The crude material was then purified by reverse phase column chromatography (using 0-60% water/ACN (0.1% NH) ₄OH) elution) and freeze-drying the pure fractions gave 6-6 as a white solid (800mg, 0.88mmol, 57.6% yield). Analytical method 5, t_R＝0.72min.,[M+H]⁺＝639.3。

Step 7.(S) -4- ((R) -3- (4-chlorobenzyl) -3- ((S) -3- ((S) -2- ((2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propanoyl) -2, 2-dimethyloxazolidine-4-carboxamide) piperidin-1-yl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid (6-7)

To intermediate 6-6(100mg, 0.156mmol) dissolved in DCM (2mL) and NMP (1mL) was added intermediate E25(52.5mg, 0.16mmol) followed by acetic acid(45uL, 0.78mmol) and the resulting mixture was stirred at room temperature for 1.5 h. Sodium triacetoxyborohydride (166mg, 0.782mmol) was then added and stirring continued at room temperature for 16 h. The reaction mixture was quenched with MeOH/water (1mL) and stirred until evolution of gas ceased. The mixture was concentrated and directly subjected to reverse phase column chromatography (with water/ACN (with 0.1% NH)₄OH) elution) and freeze-dried the pure fractions to give 6-7(105mg, 70%) as a white solid. Analytical method 2, t_R＝1.94min.,[M+H]⁺＝958.5。

Step 8.(3S,7S,10S,13R) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -6- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (6-8)

To 6-7(105mg, 0.110mmol) dissolved in DCM (150mL) were added HATU (167mg, 0.438mmol), 2, 6-lutidine (0.38mL, 3.29mmol) and HOAt (15mg, 0.11mmol), and the resulting mixture was stirred at 45 ℃ overnight. The reaction mixture was then concentrated to dryness and washed with EtOAc (100mL) and 5% NaHCO₃The aqueous solution (100mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 50mL) and brine (50mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness gave 6-8(103mg, crude). This material was used in the next step without purification. Analytical method 2: t_R＝3.18min.,[M+H]⁺＝940.7。

Step 9.(3S,7S,10S,13R) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -6- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 55)

6-8(103mg, 0.11mmol) was dissolved in ACN/H₂O (5:3) (8mL) and cooled in an ice bath. TFA (1.02mL, 13.2mmol) was added dropwise (precooled), the ice bath was removed, and the resulting mixture was stirred at room temperature for 75 minutes. Addition of saturated NaHCO₃Aqueous solution, the cloudy mixture was extracted with EtOAc (× 2). The combined organic phases were washed with brine and then with sulfuric acid Sodium was dried, filtered and concentrated. The crude oil obtained was subjected to reverse phase column chromatography (with MeCN/water (with 0.1% NH)₄OH) elution) to afford compound 55(23mg, 0.02mmol, 22.1% yield) as a white solid. Analytical method 7, t_R＝1.09min.,[M+H]⁺＝900.5。

The compounds in table 19 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 55 in example 8.26.

Table 19:

example 8.27: synthesis of (3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- ((S) -1-hydroxyethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 64)

Step 1.(S) -tert-butyl 3- ((R) -3-amino-3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluorovalerate (7-1)

To a solution of intermediate A14(2.58g, 10.1mmol) and DIPEA (4.40mL, 25.2mmol) in DMF (10mL) was added HATU (3.83g, 10.1mmol) in two portions over 5 min. The resulting mixture was stirred for 5 minutes then added to a solution of intermediate B7(3g, 10.08mmol) and DIPEA (8.80mL, 50.4mmol) in DMF (20 mL). The reaction mixture was allowed to warm to room temperature, stirred for 90 min, and then partitioned between EtOAc and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with EtOAc (× 2) and the combined organic phases were washed with saturated sodium bicarbonate solution, water (× 3) and brine, dried over sodium sulfate, Filtration and concentration gave 7-1 as an orange-brown oil (1.63g, 3.52mmol, 34.9% yield). Analytical method 5, t_R＝1.18min.,[M+H]⁺The product was used in the next step without purification 463.7.

Step 2.(S) -methyl 3- ((R) -3-amino-3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluorovalerate (7-2)

A solution of 7-1(1.63g, 3.52mmol) in anhydrous MeOH (15mL) was cooled in an ice bath. Adding SOCl₂(2.57mL, 35.2mmol) was added dropwise to the solution. After addition, the ice bath was stopped and stirring was continued at 45 ℃ for 4 hours. The reaction mixture was then cooled to room temperature and concentrated to give 7-2(1.48g), which was used in the next step without purification. Analytical method 5, t_R＝1.01min.,[M+H]⁺＝421.3。

Step 3.(S) -methyl-3- ((R) -3- ((2S,3S) -2- (((allyloxy) carbonyl) amino) -3- (tert-butoxy) butanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluorovalerate (7-4)

To a solution of Int O (457mg, 1.76mmol) in DMF (10mL) was added HATU (736mg, 1.94mmol) and DIPEA (1.85mL, 10.6 mmol). The resulting mixture was stirred for 2 min and 7-2(741mg, 1.76mmol) in DMF (5mL) was added portionwise. The reaction mixture was stirred overnight, then diluted with EtOAc and diluted with 5% NaHCO₃Wash (twice) then brine. Passing the organic phase over Na ₂SO₄Drying, filtration and concentration gave 7-4 as a brown oil (1.1g, 1.66mmol, 94% yield). The product was used in the next step without purification. Analytical method 5, t_R＝1.27min.,[M+H]⁺＝662.4。

Step 4.(S) -methyl 3- ((R) -3- ((2S,3S) -2-amino-3- (tert-butoxy) butanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluorovalerate (7-5)

A solution of 7-4(1.1g, 1.66mmol) in DCM (30mL) and N, N,1,1, 1-pentamethylsilane amine (2.66mL, 16.6mmol) was prepared by bubbling N through the solution₂The gas was degassed for 10 minutes. Addition of Pd (PPh)₃)₄(0.10g, 0.08mmol), and the resulting mixture was stirred for 20 minutes. The reaction mixture was then quenched with water and stirred for 5 minutes. Separate the phases, andthe aqueous phase was extracted with DCM. The combined organic phases are passed over Na₂SO₄Dried, filtered and concentrated to give 7-5 as a crude oil (960 mg). The product was used in the next step without purification. Analytical method 5, t_R＝1.23min.,[M+H]⁺＝578.0。

Step 5.(S) -methyl 3- ((R) -3- ((2S,3S) -3- (tert-butoxy) -2- ((R) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionamide) butyramide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoate (7-6)

To a mixture of DE1(0.74g, 1.66mmol) and 7-5(0.96g, 1.66mmol) in acetonitrile (20mL) was added DIPEA (0.87mL, 4.98mmol) followed by TBTU (0.53g, 1.66 mmol). The resulting mixture was stirred for 45 minutes. Then saturated NaHCO ₃Aqueous solution (50mL) was quenched. The mixture was concentrated to remove most of the ACN and taken up in EtOAc (100 mL). The phases were separated and the aqueous phase was back-extracted with EtOAc (× 2). The combined organic phases were washed with brine, over Na₂SO₄Dried, filtered and concentrated in vacuo. The crude residue was purified by normal phase flash column chromatography on silica gel (eluting with 0-10% DCM/MeOH) to give 7-6 as a white solid (1.09g, 1.09mmol, 65.4% yield). Analytical method 5, t_R＝1.40min.,[M+H]⁺＝1002.6。

Step 6.(S) -3- ((R) -3- ((2S,3S) -3- (tert-butoxy) -2- ((R) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionamide) butyramide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (7-7)

To a solution of 7-6(1.09g, 1.09mmol) in ACN (7.4mL) and water (0.4mL) was added triethylamine (1.52mL, 10.9mmol) followed by LiBr (1.89g, 21.7 mmol). The resulting mixture was heated to 45 ℃ and stirred for 30 minutes. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was partitioned with EtOAc/water and the phases were separated. The aqueous phase was acidified with 0.5N HCl to a pH of about 6. The aqueous layer was extracted again. The combined organic phases were washed with brine, over Na₂SO₄Dried, filtered and concentrated to give 7-7(980mg, 0.99mmol, 91% yield) as a yellow gummy solid Rate). The product was used in the next step without purification. Analytical method 5, t_R＝0.95min.,[M+H]⁺＝988.6。

Step 7.(3S,7S,10S,13R) -10- ((S) -1- (tert-butoxy) ethyl) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (7-8)

To a solution of 7-7(980mg, 0.99mmol) in DCM (900mL) was added 2, 6-lutidine (2.31mL, 19.8mmol), HOAt (135mg, 0.99mmol) and HATU (1.51g, 3.96mmol) and the resulting mixture was heated at 40 deg.C (heating bath) overnight. The reaction mixture was cooled to room temperature and quenched with NaHCO₃And a brine wash. Passing the organic phase over Na₂SO₄Drying, filtration and concentration gave 7-8 as a crude oil (1 g). The product was used in the next step without purification. Analytical method 5, t_R＝1.41min.,[M+H]⁺＝970.7。

Step 8.(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- ((S) -1-hydroxyethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 64)

To a mixture of 7-8(1g, 1.03mmol) in DCM (2.6mL) was added TFA (3.17mL, 41.2mmol) dropwise at 0 deg.C. The resulting mixture was stirred for 4 hours, then concentrated in vacuo and purified by reverse phase column chromatography (with 45% -80% water/ACN (with 0.1% NH) ₄OH) elution) and concentration of the pure fractions gave compound 64 as a white solid (180mg, 0.187mmol, 18.2% yield). Analytical method 7, t_R＝1.02min.,[M+H]⁺＝914.3。

The compounds in table 20 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 64 in example 8.27.

Table 20:

example 8.28: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 32)

Step 1.(R) -3- (4-chlorobenzyl) -1- ((4-nitrophenyl) sulfonyl) piperidin-3-amine, (S) -tert-butyl 4- (((R) -3- (4-chlorobenzyl) -1- ((4-nitrophenyl) sulfonyl) piperidin-3-yl) carbamoyl) -2, 2-dimethyloxazolidine-3-carboxylate (8-1)

To a suspension of B7(370mg, 1.24mmol) in DCM (10mL) was added TEA (1.73mL, 12.4mmol) and nitrobenzenesulfonyl chloride (275mg, 1.24 mmol). The resulting solution was stirred at room temperature for 10 minutes, and then (S) -3- (tert-butoxycarbonyl) -2, 2-dimethyloxazolidine-4-carboxylic acid (335mg, 1.37mmol) and HATU (520mg, 1.37mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, then additional (S) -3- (tert-butoxycarbonyl) -2, 2-dimethyloxazolidine-4-carboxylic acid (0.5 eq) and HATU (0.5 eq) were added. The mixture was diluted with EtOAc (50mL) and 2 × 50mL with 5% NaHCO ₃The solution and brine washes. The organic phase was dried over sodium sulfate, filtered and concentrated to give a crude oil. The material was purified by flash column chromatography on silica gel (eluting with 0-100% EtOAc/heptane) to give 8-1 as a white foam (810mg, 1.27 mmol). Analytical method 5, t_R＝1.30min.,[M+H]⁺-100＝537.2。

Step 2.(S) -tert-butyl 4- (((R) -3- (4-chlorobenzyl) -1- ((4-nitrophenyl) sulfonyl) piperidin-3-yl) (methyl) carbamoyl) -2, 2-dimethyloxazolidine-3-carboxylate (8-2)

Under nitrogen atmosphere at 0To a solution of 8-1(780mg, 1.22mmol) in anhydrous DMF (10mL) at deg.C was added NaH (60% in mineral oil, 112mg, 2.80 mmol). The resulting mixture was stirred at 0 ℃ for 60 minutes. MeI (0.31mL, 4.90mmol) was added and stirring continued at 0 deg.C for 1.5 h. The reaction mixture was washed with saturated NaHCO₃And quenching with water to obtain slurry. The grey precipitate was collected by vacuum filtration and redissolved in EtOAc. The organic phase was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 8-2 as a yellow foam (690mg, 1.06mmol, 87% yield). The product was used in the next step without further purification. Analytical method 5, t_R＝1.34min.,MS[M+H-100]⁺＝551.1。

Step 3 (S) -2-amino-N- ((R) -3- (4-chlorobenzyl) -1- ((4-nitrophenyl) sulfonyl) piperidin-3-yl) -3-hydroxy-N-methylpropanamide (8-3)

To a solution of 8-2(680mg, 1.04mmol) in DCM (10mL) was added TFA (5mL, 64.9mmol) at 0 deg.C. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. Water (0.06mL, 3.13mmol) was added and stirring was continued for another 1 h. The reaction mixture was concentrated to remove excess TFA. Using 15mL of 2N Na₂CO₃The resulting crude oil was diluted and extracted with 2 × 20mL of DCM. The combined organic phases were washed with saturated NaHCO₃Washed, dried over sodium sulfate, filtered and concentrated to give 8-3 as a yellow foam (534mg, 1.04mmol, 100% yield). The product was used in the next step without further purification. Analytical method 5, t_R＝0.96min.,[M+H]⁺＝511.2。

Step 4.(S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -N- ((R) -3- (4-chlorobenzyl) -1- ((4-nitrophenyl) sulfonyl) piperidin-3-yl) -3-hydroxy-N-methylpropanamide (8-4)

To a suspension of 8-3(482mg, 1.05mmol) in ACN (15mL) was added DIPEA (0.55mL, 3.14mmol) and TBTU (336mg, 1.05 mmol). The resulting mixture was stirred at room temperature for 2 minutes, then DE1 solution (534mg, 1.05mmol in 10mL ACN) was added. The reaction mixture was stirred for 1 hour, then saturated NaHCO was added ₃Solutions andwater (50 mL each). The mixture was then extracted with 2x50mL of DCM. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give 13-4 as a yellow foam (1.06g, 0.83mmol, 79% yield). The product was used directly in the next step without further purification. Analytical method 5, t_R＝1.22min.,[M+H]⁺＝953.5。

Step 5.(S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -N- ((R) -3- (4-chlorobenzyl) piperidin-3-yl) -3-hydroxy-N-methylpropanamide (8-5)

To a solution of 8-4(482mg, 0.51mmol) in MeOH (25mL) was added thioglycolic acid (0.14mL, 2.02mmol) and Cs₂CO₃(1.15g, 3.54 mmol). The resulting mixture was stirred at room temperature for 3.5 hours, diluted with 150ml of water, and extracted with 2x100mL DCM (a small amount of brine may be required to aid partitioning). The combined organic phases were dried over sodium sulfate, filtered and concentrated to give 8-5(388mg, 0.505mmol, ca. quantitative yield) as a yellow foam (analytical method 5, t_R＝1.15min；[M+H]⁺768.3) containing about 10% of 8-9 (analytical method 5, t)_R1.23 min). The product was used directly in the next step without further purification.

Step 6.2- ((R) -4- (tert-butoxy) -2- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-oxobutyl) pyridine 1-oxide (8-6)

To a solution of A15(135mg, 0.48mmol) in 5mL ACN was added DIPEA (0.34mL, 1.92mmol) and HATU (183mg, 0.48 mmol). The resulting mixture was stirred at room temperature for 5 minutes. Then added to a solution of 8-5(369mg, 0.48mmol) in 6mL ACN. The reaction was continued for 30 minutes. Then 50mL of 5% NaHCO₃And (4) quenching. The mixture was extracted with 2 × 50mL EtOAc. The combined EtOAc phases were washed with brine, dried over sodium sulfate, filtered and concentrated to give 8-6 as a yellow solid (495mg, 0.480mmol, assuming quantitative yield), which was used in the next step without further purification. Analysis ofMethod 5, t_R＝1.15min.,[M+H]⁺＝1031.8。

Step 7.2- ((R) -2- (carboxymethyl) -3- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-oxapropyl) pyridine 1-oxide (8-7)

To a solution of 8-6(495mg, 0.480mmol) in DCM (5mL) was added TFA (5mL, 64.9 mmol). The resulting mixture was stirred at room temperature for 1.5 hours, then concentrated. The crude product was taken up in DMSO and purified by reverse phase column chromatography (with 0-50% water/ACN (with 0.1% NH)₄OH) elution) was directly purified, yielding 8-7(125mg, 0.11mmol, 23% yield) after freeze drying of the pure fractions. Analytical method 5, t _R＝0.78min.,[M+H]⁺＝975.3。

Step 8.2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine 1-oxide (8-8)

To a solution of 8-7(125mg, 0.13mmol) in DCM (120mL) were added 2, 6-lutidine (0.45mL, 3.84mmol), HOAt (17.4mg, 0.13mmol), and HATU (195mg, 0.51 mmol). The resulting mixture was refluxed in a heating bath at 48 ℃ for 4 hours, cooled to room temperature, and then concentrated. The crude residue was taken up in EtOAc (50mL) and 5% NaHCO₃The aqueous solution (50mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 50mL) and brine (50mL) were washed over Na₂SO₄Drying, filtration and concentration to dryness gave 8-8(123mg, 0.13mmol, assuming quantitative yield). The product was used in the next step without further purification. Analytical method 5, t_R＝0.96min.,[M+H]⁺＝957.4。

Step 9.(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 32)

To a solution of 8-8(123mg, 0.13mmol) in THF (15mL) was added saturated NH₄Cl solution (5mL), zinc powder (537mg, 8.22mmol) and citric acid (444mg, 2.31 mmol). The resulting mixture was stirred at room temperature for 30 minutes to obtain a two-phase mixture. The organic phase was collected and the aqueous phase was extracted with DCM. The combined organic phases were concentrated and the residue was taken up in DCM and washed with 5% NaHCO₃The solution was washed, dried over sodium sulfate, filtered and concentrated. The crude product was taken up in DMSO and passed HPLC (0.1% NH)₄OH as buffer) and freeze-dried the pure fraction to give compound 32(20mg, 0.02mmol, 16% yield). Analytical method 2, t_R＝2.59min,[M+H]⁺＝941.5。

Example 8.29: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 13)

Step 1.(R) -tert-butyl 3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (9-1)

To a solution of intermediate J (0.50g, 1.13mmol) and DE2(0.57g, 1.24mmol) in ACN (25mL) was added DIPEA (0.59mL, 3.38mmol) and TBTU (0.40g, 1.24 mmol). The resulting mixture was stirred at room temperature for 0.5 h with half-saturated NaHCO₃The solution (100mL) was diluted and extracted with 100mL EtOAc. The organic phase was washed with 5% NaHCO₃And brine, dried over sodium sulfate, filtered and concentrated to give 9-1 as a yellow foam (1g, quantitative yield). Analytical method 5, t_R＝1.33min.,[M+H]⁺882.7 the material was used in the next step without purification.

Step 2.(S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -N- ((R) -3- (4-chlorobenzyl) piperidin-3-yl) -3-methoxy-N-methylpropanamide hydrochloride (9-2)

To a cooled mixture of 9-1(1g, 1.13mmol) in anhydrous methanol (11mL) and in an ice bath was added cold HCl in dioxane (4N, 11.3mL, 45.1 mmol). The ice bath was removed and the resulting mixture was slowly warmed to room temperature and stirred for 1.5 hours. Additional methanol (11mL) and HCl (20 equivalents, 4N in dioxane) were added and stirring continued at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated again. This procedure was repeated three times to give 9-2 as a yellow solid (0.97g, ca. quantitative yield). Analytical method 5, t _R＝1.17min.,[M+H]⁺782.4 the material was used in the next step without purification.

Step 3.(R) -tert-butyl 4- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((6-methylpyridin-2-yl) methyl) -4-oxobutyrate (9-3)

To a solution of 9-2(0.48g, 0.56mmol) in 10mL ACN was added DIPEA (0.30mL, 1.69mmol) and intermediate A17(0.19g, 0.68 mmol). The resulting mixture was stirred at room temperature and HATU (0.26g, 0.68mmol) was added. The reaction mixture was stirred for 1 hour with 50mL of 5% NaHCO₃The solution was quenched and extracted with 2 × 50mL EtOAc. The combined organic phases were washed with 5% NaHCO₃The solution and brine washes. The mixture was dried over sodium sulfate, filtered, and concentrated to give 9-3 as a yellow solid (0.589g, 0.56mmol, assuming quantitative yield). The crude product was used in the next step without purification. Analytical method 5, t_R＝1.34min.,[M+H]⁺＝1043.7。

Step 4.(R) -4- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((6-methylpyridin-2-yl) methyl) -4-oxobutanoic acid (9-4)

To a solution of 9-3(589mg, 0.56mmol) in DCM (5mL) at 0 deg.C was added TFA (5mL, 64.9 mmol). The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Toluene was added and the mixture was concentrated again (step repeated once more) to remove excess TFA. The crude material was then purified by reverse phase column chromatography (with 0-50% water/ACN (with 0.1% NH)₄OH) elution) and freeze-drying the pure fractions gave 9-4(153mg, 0.16mmol, 28% yield) as a white powder. Analytical method 5, t_R＝0.82min.,[M+H]⁺＝987.3。

Step 5.(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 13)

To a solution of 9-4(153mg, 0.16mmol) in anhydrous DCM (100mL) were added 2, 6-lutidine (0.54mL, 4.65mmol), HOAt (21mg, 0.16mmol), and HATU (236mg, 0.62 mmol). The resulting mixture was heated to reflux in a 48 ℃ heating bath overnight, then cooled to room temperature and concentrated to dryness. The residue obtained was taken up in EtOAc (50mL) and 5% NaHCO ₃The aqueous solution (50mL) was partitioned. The organic phase was collected with 5% NaHCO₃Aqueous (2 × 50mL) and brine (50mL) were washed over Na₂SO₄Dried, filtered and concentrated. The crude oil was taken up in ACN and purified by HPLC (elution with 0-100% water/ACN) to afford compound 13(52mg, 0.05mmol, 33% yield) after freeze drying of the pure fractions. Analytical method 2, t_R＝2.89min.,[M+H]⁺＝969.7。

The compounds in table 21 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 13 in example 8.29.

Table 21:

example 8.30: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 57)

Step 1.2- ((R) -4- (tert-butoxy) -2- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-oxobutyl) pyridine-1-oxide (10-1)

To a solution of A15(40mg, 0.143mmol) in 2mL ACN were added DIPEA (0.08mL, 0.48mmol) and HATU (54mg, 0.14 mmol)). The resulting mixture was stirred at room temperature for 5 minutes, then a solution of 9-2(93mg, 0.12mmol) in 2ml ACN was added. The reaction mixture was stirred overnight with 15ml of 5% NaHCO ₃Quenched and extracted with EtOAc. The combined organic phases were washed with 5% NaHCO₃Washed with brine, dried over sodium sulfate, filtered and concentrated to give 10-1 as a yellow solid (124mg, 0.12mmol, ca. quantitative yield). The crude product was used in the next step without further purification. Analytical method 5, t_R＝1.20min.,[M+H]⁺＝1045.5。

Step 2.2- ((R) -2- (carboxymethyl) -3- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-oxapropyl) pyridine-1-oxide (10-2)

To a solution of 10-1(124mg, 0.12mmol) in DCM (2mL) was added TFA (2mL, 26.1mmol), and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was then concentrated and the crude material was purified by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH) elution) purification, after freeze-drying of the pure fractions10-2(26mg, 0.03mmol, 22% yield) was obtained. Analytical method 5, t_R＝0.77min.,[M+H]⁺＝989.6。

Step 3.2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine-1-oxide (10-3)

To a solution of 10-2(26mg, 0.03mmol) in DCM (20mL) were added 2, 6-lutidine (0.09mL, 0.79mmol), HOAt (4mg, 0.03mmol), and HATU (40mg, 0.11 mmol). The resulting mixture was heated to reflux in a heating bath at 48 ℃ for 1.5 hours, then cooled to room temperature and concentrated. The residue was taken up in EtOAc and 5% NaHCO₃The aqueous solution was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 15mL) and brine (15mL) were washed over Na₂SO₄Drying, filtration and concentration gave 10-3(25mg, 0.03mmol, ca. quantitative yield), which was used in the next step without further purification. Analytical method 5, t_R＝1.07min.,[M+H]⁺＝971.4。

Step 4.(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (compound 57)

To a solution of 10-3(25mg, 0.03mmol) in THF (5mL) was added saturated NH₄Cl solution (1.7mL), zinc (109mg, 1.66mmol) and citric acid (90mg, 0.47 mmol). The resulting mixture was stirred at room temperature for 30 minutes to obtain a two-phase mixture. The organic phase was collected and the aqueous phase was extracted with DCM. The combined organic phases were concentrated and the residue was taken up in DCM and washed with 5% NaHCO ₃The solution was washed, dried over sodium sulfate, and concentrated. The crude product was taken up in DMSO and purified by HPLC (with 0-100% water/ACN (with 0.1% NH)₄OH) elution) to afford compound 57(12mg, 0.01mmol, 48% yield). Analytical method 2, t_R＝2.77min.,[M+H]⁺＝955.4。

The compounds in table 22 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 57 in example 8.30.

Table 22:

example 8.31: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 94)

Step 1.(R) -tert-butyl 3- ((S) -2- ((S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propionamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (11-1)

Step 1-1: to a solution of intermediate J (252mg, 0.57mmol) in DMF was added DIPEA (0.2mL, 1.14mmol), Fmoc-Ala-OH (187mg, 0.60mmol) and HATU (228mg, 0.60 mmol). The resulting mixture was stirred at room temperature overnight.

Step 1-2: 4-methylpiperidine (1.35mL, 11.4mmol) was then added and stirring was continued for 1 hour to complete the deprotection step. The resulting mixture was diluted with 50mL EtOAc and with 5% NaHCO ₃(3 × 50mL) washing. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was taken up in a mixture of DMSO/ACN and chromatographed by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH) elution) and freeze-dried the pure fractions to give 11-1(170mg, 0.27mmol, 47% yield). Analytical method 5, t_R＝1.04min.,[M+H]⁺＝511.1。

Step 2.(R) -tert-butyl 3- ((S) -2- ((S) -2- ((4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) amino) propionamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (11-2)

To a mixture of 11-1(170mg, 0.33mmol) and E14(173mg, 0.47mmol) in DCM (5mL) was added AcOH (0.08mL, 1.33mmol), and the resulting mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (282mg, 1.33mmol) was added and stirring was continued for 1.5 h. EtOAc was added and the organic phase was purified with 3 × 50mL of 5% NaHCO₃Washed with brine and then Na₂SO₄Drying, filtration and concentration gave 11-2(288mg, 0.33mmol, ca. quantitative yield) as a yellow oil. The crude product was used in the next step without purification. Analytical method 5, t_R＝1.30min.,[M+H]⁺＝865.3。

Step 3.(S) -2- ((S) -2- ((4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) amino) propionamide) -N- ((R) -3- (4-chlorobenzyl) piperidin-3-yl) -3-methoxy-N-methylpropanamide (11-3)

To a solution of 11-2(288mg, 0.33mmol) in dry methanol (5mL) was added cold HCl in dioxane (5mL, 20.0 mmol). The resulting mixture was stirred at room temperature for 4 hours, then concentrated. The crude residue obtained (which was taken up in toluene and concentrated) was taken up in about quantitative yield. The product was used in the next step without purification. Analytical method 5, t_R＝1.10min.,[M+H]⁺＝765.5。

Step 4.2- ((R) -4- (tert-butoxy) -2- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) amino) propionamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-oxobutyl) pyridine 1-oxide (11-4)

To a solution of 11-3(279mg, 0.33mmol) in 10mL ACN were added DIPEA (0.17mL, 1.0mmol), A15(140mg, 0.50mmol) and HATU (164mg, 0.43 mmol). The resulting mixture was stirred at room temperature for 2 hours, then 50mL of 5% NaHCO₃Quenched and extracted with 2 × 50mL EtOAc. The combined organic phases were washed with 5% NaHCO₃And brine, dried over sodium sulfate, filtered, and concentrated to give 11-4 as a yellow oil (342mg,0.33mmol, approx. quantitative yield). The product was used in the next step without further purification. Analytical method 5, t _R＝1.13min.,[M+H]⁺＝1028.7。

Step 5.2- ((R) -2- (carboxymethyl) -3- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) amino) propionamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-oxapropyl) pyridine 1-oxide (11-5)

To a solution of 11-4(342mg, 0.33mmol) in DCM (5mL) was added TFA (5mL, 64.9mmol), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a crude residue, which was taken up in toluene and concentrated again. This was repeated once more. The crude product was purified by reverse phase column chromatography (with 0-50% water/ACN (with 0.1% NH)₄OH) elution) and freeze-drying the pure fractions to give 11-5 as a white fluffy powder (135mg, 0.14mmol, 38% yield). Analytical method 5, t_R＝0.76min.,[M+H]⁺＝972.3。

Step 6.2- (((3R,7S,10S,13R) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine 1-oxide (11-6)

To a solution of 11-5(135mg, 0.14mmol) in anhydrous DCM (100mL) were added 2, 6-lutidine (0.49mL, 4.16mmol), HOAt (19mg, 0.14mmol), and HATU (211mg, 0.56 mmol). The resulting mixture was refluxed overnight in a heating bath at 48 ℃, then brought to room temperature, and concentrated to dryness. The residue obtained was taken up in EtOAc (50mL) and 5% NaHCO ₃The aqueous solution (50mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 50mL) and brine (50mL) were washed over Na₂SO₄Drying, filtration, and concentration to dryness gave 11-6(133mg, 0.14mmol, ca. quantitative yield). The product was used in the next step without further purification. Analytical method 5, t_R＝1.02min.,[M+H]⁺/2＝477.8。

Step 7.(3R,7S,10S,13R) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 94)

To a solution of 11-6(133mg, 0.14mmol) in THF (10mL) was added saturated NH₄Cl (3.34mL), zinc powder (583mg, 8.91mmol), and citric acid (482mg, 2.51 mmol). The resultant was stirred at room temperature for 90 minutes to obtain a two-phase mixture. The organic phase was separated and the remaining aqueous phase was washed with DCM. The combined organic phases were concentrated and the residue was taken up in DCM and washed with 5% NaHCO₃And (6) washing. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was taken up in ACN and purified by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH) elution) and concentration of the pure fractions gave compound 94(51mg, 0.05mmol, 37% yield). Analytical method 2, t _R＝2.66min.,[M+H]⁺＝938.4。

The compounds in table 23 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 94 in example 8.31. Preparation of compound 174 according to example 8.31, steps 2-7

Table 23:

example 8.32: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 1)

Step 1.2- ((R) -2- ((R) -3-amino-3- (4-chlorobenzyl) piperidine-1-carbonyl) -4- (tert-butoxy) -4-oxobutyl) pyridine 1-oxide (12-1)

To a solution of A15(1.696g, 6.03mmol) in anhydrous ACN (40mL) were added DIPEA (4.74mL, 27.1mmol), E37(1.80g, 6.03mmol) and HATU (2.98g, 7.84 mmol). The resulting mixture was stirred at room temperature overnight, then in EtOAc (100mL) and 5% NaHCO₃The aqueous solution (100mL) was partitioned. Passing the organic phase over Na₂SO₄Dried, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (eluting with 0-10% DCM/MeOH) to give 12-1 as a yellow solid after concentration of the pure fractions (2.63g, 5.39mmol, 89% yield). Analytical method 5, t _R＝0.92min.,[M+H]⁺＝488.4。

Step 2.2- ((R) -3- ((R) -3-amino-3- (4-chlorobenzyl) piperidin-1-yl) -2- (carboxymethyl) -3-oxapropyl) pyridine 1-oxide (12-2)

To 12-1(2.63g, 5.39mmol) in dry DCM (8mL) was added TFA (8.30mL, 108 mmol). The resulting mixture was stirred at room temperature for 6 hours, then concentrated and dried well to give 12-2(2.9g, 5.39mmol, ca. quantitative yield). The crude product was used in the next step without purification. Analytical method 5, t_R＝0.50min.,[M+H]⁺＝432.3。

Step 3.2- ((R) -2- ((R) -3-amino-3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-methoxy-4-oxobutyl) pyridine 1-oxide (12-3)

To a solution of 12-2(2.9g, 5.39mmol) in anhydrous MeOH (13mL) was added 4M HCl in dioxane (13.5mL, 53.9 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH) elution) and concentration of the pure fractions gave 12-3(766mg, 1.72mmol, 32% yield). Analytical method 5, t_R＝0.75min.,[M+H]⁺＝446.3。

Step 4.2- ((R) -2- ((R) -3- ((S) -3- ((S) -2-aminopropionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-methoxy-4-oxobutyl) pyridine 1-oxide (12-4)

To Fmoc-Ala-Ser [ psi (Me, Me) pro ]To a solution of-OH (403mg, 0.92mmol) in DMA (5mL) were added HATU (350mg, 0.92mmol) and DIPEA (0.21mL, 1.20 mmol). The solution was stirred at room temperature for 2 minutes, then a solution of 12-3(410mg, 0.92mmol) in DMA (3mL) was added. The resulting mixture was stirred at room temperature overnight, then 4-methylpiperidine (3mL) was added. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness under reduced pressure. The crude material was purified by reverse phase column chromatography (with 0-60% water/ACN (with 0.1% NH)₄OH) elution) and dried the pure fractions freely to give 12-4(360mg, 0.60mmol, 61% yield). Analytical method 5, t_R＝0.84min.,[M+H]⁺＝644.5。

Step 5.2- ((R) -2- ((R) -3- ((S) -3- ((S) -2- ((4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) amino) propionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-methoxy-4-oxobutyl) pyridine 1-oxide (12-5)

To a mixture of 12-4(360mg, 0.60mmol) and E37(332mg, 0.84mmol) in DCM (15mL) was added AcOH (0.13mL, 2.24 mmol). The resulting mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (592mg, 2.79mmol) was added. The reaction mixture was stirred for 2 hours, then EtOAc (60mL) was added. The organic phase was washed with 5% Na ₂CO₃Washed with aqueous solution (50mL x2) over Na₂SO₄Drying, filtration and concentration to dryness gave 12-5 as a brown oil (572mg, 0.60mmol, crude). The product was used in the next step without purification. Analytical method 5, t_R＝1.18min.,[M+H]⁺＝1023.6。

Step 6.2- ((R) -2- (carboxymethyl) -3- ((R) -3- ((S) -3- ((S) -2- ((4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) amino) propionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-oxapropyl) pyridine 1-oxide (12-6)

To a mixture of 12-5(572mg, 0.60mmol) in dioxane (10mL) and H₂To the mixture in O (2.5mL) and cooled to 0 deg.C was added 1M NaOH (2.23mL, 2.2)3 mmol). The resulting mixture was stirred at room temperature for 2 hours. Additional NaOH (1M, up to 3.3mL) was added and stirring was continued at room temperature until LCMS showed consumption of the starting material. The reaction mixture was washed with AcOH (0.96mL, 16.8mmol) and 50mL NaHCO₃Quenched and extracted with EtOAc (× 2). Brine was added to the aqueous phase and back extracted again with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude material was purified by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH) elution) and freeze-drying of the pure fractions gave 12-6(436mg, 0.43mmol, 77% yield). Analytical method 5, t _R＝0.84min.,[M+H]⁺＝1009.4。

Step 7.2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine 1-oxide (12-7)

Step 7-1: to a solution of 12-6(436mg, 0.43mmol) in DCM (250mL) was added 2, 6-lutidine (1.51mL, 12.9mmol), HOAt (58.8mg, 0.43mmol), and HATU (657mg, 1.73 mmol). The resulting mixture was heated to reflux in a heating bath at 48 ℃ for 19 hours, then cooled to room temperature and concentrated to dryness. The residue obtained was taken up in EtOAc (100mL) and 5% NaHCO₃The aqueous solution (50mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (2 × 50mL) and brine (50mL) were washed over Na₂SO₄Dried, filtered and concentrated to dryness under reduced pressure. Analytical method 5: t_R＝1.17min；[M+H]⁺＝991.3。

Step 7-2: to the ACN/H₂The crude product from step 7-1, in a mixture of O (5:3) (16mL) and cooled to 0 ℃ in an ice bath, was added dropwise to a pre-cooled solution of TFA (3.9mL, 51.3mmol) and the resulting mixture was stirred at room temperature for 75 minutes. Addition of saturated NaHCO₃/1M Na₂CO₃The reaction was basified and the resulting slurry was extracted with EtOAc (× 2). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to give 12-7(137mg, 0.14mmol, ca. quantitative yield). The product does not need to be Further purification was carried out and used directly in the next step. Analytical method 5, t_R＝1.02min.,[M+H]⁺＝951.6。

Step 9.(3R,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 1)

To a solution of 12-7(137mg, 0.14mmol) in THF (40mL) was added saturated NH₄Cl (13.3mL), zinc powder (1.8g, 27.1mmol) and citric acid (1464mg, 7.62mmol), and the resulting mixture was stirred at room temperature for 30 minutes to give a biphasic mixture. The organic phase was collected and the remaining aqueous phase was washed with 50mL of DCM. The combined organic phases were concentrated to dryness, the residue taken up in DCM and washed with 5% NaHCO₃And (4) washing the solution. The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was purified by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH) elution) and freeze-dried the pure fractions to give compound 1(137mg, 0.14mmol, 34% yield). Analytical method 2, t_R＝2.71min.,[M+H]⁺＝935.7。

Example 8.33: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 18)

Step 1.(R) -tert-butyl 3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propanamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (14-1)

To intermediate DE1(59.3mg, 0.134mmol) in ACN (5mL) was added DIPEA (0.070mL, 0.401mmol) and TBTU (43.0mg, 0.134 mmol). Mixing the obtained mixtureAfter stirring at room temperature for 5 min, intermediate G (57mg, 0.134mmol) was added. The reaction mixture was stirred for 1.5 hours, then with 10mL saturated NaHCO₃And 10mL of water and extracted with 2 × 15mL DCM. The combined organic phases were dried over sodium sulfate and concentrated to give 14-1 as an oil (114mg, 0.134 mmol). The oil was used directly in the next step without further purification. Analytical method 5, t_R＝1.03min.,[M+H]⁺＝850.4。

Step 2.(S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propanamide) -N- ((R) -3- (4-chlorobenzyl) piperidin-3-yl) -3-hydroxy-N-methylpropanamide (14-2)

To a solution of 14-1(114mg, 0.134mmol) in DCM (3mL) was added TFA (1.032mL, 13.40 mmol). The resulting solution was stirred at room temperature for 1 hour, then concentrated to dryness. The resulting oil (14-2, 101mg, 0.135mmol, ca. quantitative yield) was used in the next step without further purification. Analytical method 5, t _R＝1.13min.,[M+H]⁺＝750.4。

Step 3.2- ((R) -4- (tert-butoxy) -2- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propanamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-oxobutyl) pyridine 1-oxide (14-3)

To a solution of A15 in 3mL ACN was added DIPEA (0.09mL, 0.54mmol) and HATU (51.2mg, 0.14 mmol). The resulting mixture was stirred at room temperature for 5 minutes, then a solution of 14-2(101mg, 0.135mmol) in 2mL ACN was added. The reaction mixture was stirred for 30 minutes and then with NaHCO₃The solution was quenched and extracted with 2 × 15mL EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give 14-3 as a yellow oil (136mg, 0.135mmol, ca. quantitative yield). The product was used in the next step without further purification. Analytical method 5, t_R＝1.13min.,[M+H]⁺＝1013.7。

Step 4.2- ((R) -2- (carboxymethyl) -3- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propanamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-oxapropyl) pyridine 1-oxide (14-4)

To a solution of 14-3(136mg, 0.135mmol) in DCM (2mL) was added TFA (2.07mL, 26.8mmol), and the resulting mixture was stirred at room temperature for 2 hours, then concentrated to dryness under reduced pressure. The crude material was taken up in DMSO and chromatographed by reverse phase column chromatography (with 0-50% water/ACN (with 0.1% NH) ₄OH) elution) and freeze-dried the pure fractions to give 14-4(47mg, 0.05mmol, 34% yield). Analytical method 5, t_R＝0.78min.,[M+H]⁺＝957.4。

Step 5.2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine 1-oxide (14-5)

To a solution of 14-4(40mg, 0.04mmol) in DCM (50mL) were added 2, 6-lutidine (0.15mL, 1.25mmol), HOAt (5.7mg, 0.04mmol), and HATU (63.5mg, 0.17 mmol). The resulting mixture was heated to reflux at 48 ℃ for 4 hours, then cooled to room temperature and concentrated. The residue obtained was taken up in EtOAc (15mL) and 5% NaHCO₃(15 mL). The organic phase was washed with 5% NaHCO₃(2X15mL) and brine (15mL) over Na₂SO₄Drying, filtration, and concentration to dryness under reduced pressure gave 14-5(43mg, 0.04mmol, ca. quantitative yield). The product was used in the next step without further purification. Analytical method 5, t_R＝0.97min.,[M+H]⁺＝939.4。

Step 6.(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 18)

To a solution of 14-5(43mg, 0.04mmol) in THF (5mL) was added saturated NH₄Cl (1.7mL), zinc powder (194mg, 2.97mmol) and citric acid (160mg, 0.84 mmol). The resulting mixture was stirred at room temperature for 30 minutes to obtain a two-phase mixtureA compound (I) is provided. The organic phase was collected and the remaining aqueous mixture was washed with 5mL of DCM. The combined organic phases were concentrated to dryness and the resulting residue was taken up in DCM and washed with 5% NaHCO₃And (4) washing the solution. The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was purified by HPLC (with 0-100% water/ACN (with 0.1% NH)₄OH as buffer) and freeze-dried the pure fractions to give compound 18(12mg, 0.01mmol, 27% yield) as a white powder. Analytical method 2, t_R＝2.60min.,[M+H]⁺＝923.6。

Example 8.34: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- ((difluoromethoxy) methyl) -7-methyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 30)

Step 1.2- ((R) -2- ((R) -3- ((S) -2-amino-3- (difluoromethoxy) propanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4- (tert-butoxy) -4-oxobutyl) pyridine 1-oxide (15-1)

To a solution of 12-1(250mg, 0.51mmol) in THF (5mL) was added intermediate P (773mg, 2.05mmol) and DIPEA (0.54mL, 3.07mmol), followed by DMT-MM (354mg, 1.28 mmol). The resulting mixture was stirred at room temperature for 1 hour. 4-methylpiperidine (0.61mL, 5.12mmol) was then added. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness under reduced pressure. Subjecting the crude material to reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH) elution) and freeze-dried the pure fractions to give 15-1(131mg, 0.21mmol, 41% yield). Analytical method 5, t_R＝1.27min.,[M+H]⁺＝625.3。

Step 2.2- ((R) -2- (carboxymethyl) -3- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) amino) propanamide) -3- (difluoromethoxy) propanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-oxapropyl) pyridine 1-oxide (15-2)

To a solution of 15-1(187mg, 0.30mmol) in DCM (15mL) were added DIPEA (0.16mL, 0.90mmol), 30-1(140mg, 0.30mmol) and HATU (114mg, 0.30mmol), and the resulting mixture was stirred at room temperature for 3 hours. TFA (4.60mL, 59.7mmol) was added and stirring was continued for 90 min. The reaction mixture was then concentrated under reduced pressure and the crude material was purified by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH) ₄OH) elution) and freeze-dried the pure fractions to give 15-2(183mg, 0.18mmol, 60% yield). Analytical method 5, t_R＝0.82min.,[M+H]⁺＝1019.7。

Step 3.2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- ((difluoromethoxy) methyl) -7-methyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine 1-oxide (15-3)

To a solution of 15-2(167mg, 0.16mmol) in DCM (100mL) were added 2, 6-lutidine (0.57mL, 4.91mmol), HOAt (22.3mg, 0.16mmol) and HATU (249mg, 0.66mmol) and the resulting mixture was heated to reflux at 48 ℃ overnight. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was taken up in EtOAc (100mL) and 5% NaHCO₃(100 mL). The organic phase was washed with 5% NaHCO₃(2X50mL) and brine (50mL) over Na₂SO₄Drying, filtration, and concentration to dryness under reduced pressure gave 15-3(164mg, 0.16mmol, ca. quantitative yield). The product was used in the next step without further purification. Analytical method 5, t_R＝1.16min.,[M+H]⁺＝1001.6。

Step 4.(3R,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- ((difluoromethoxy) methyl) -7-methyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 30)

To a solution of 15-3(164mg, 0.16mmol) in THF (20mL) was added saturated NH₄Cl (6.7mL), Zinc powder (685mg, 10.5 mm)ol) and citric acid (566mg, 2.95 mmol). The resulting mixture was stirred at room temperature for 30 minutes to obtain a two-phase mixture. The organic phase was collected and the remaining aqueous phase was washed with 50mL of DCM. The combined organic phases were concentrated to dryness and the resulting residue was taken up in DCM and washed with 5% NaHCO₃And (4) washing the solution. The organic phase was separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH) elution) to yield the desired product with a small amount of impurities. The material was again passed through HPLC (with 0-100% water/ACN (with 0.1% NH)₄OH as modifier) was eluted, and the pure fractions were lyophilized to give compound 30(63mg, 0.06mmol, 37% yield) as a white powder. Analytical method 2, t_R＝3.04min.,[M+H]⁺＝985.4。

Example 8.35: synthesis of 2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine 1-oxide (Compound 66)

Step 1.(S) -3- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -L-alanyl) -N- ((R) -3- (4-chlorobenzyl) piperidin-3-yl) -2, 2-dimethyloxazolidine-4-carboxamide (16-1) and (S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionamide) -N- ((R) -3- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) Benzyl) piperidin-3-yl) -3-hydroxypropionamide (16-2)

4N HCl in dioxane (1.0mL, 4.00mmol) was added to 1-3(105.2mg, 0.12mmol) in a round bottom flask equipped with a magnetic stir bar. Additional dioxane (3mL) was then added in one portion via syringe. The resulting mixture was stirred at room temperature for 2.5 hours, then concentrated in vacuo to give 88mg of a white solid which was purified by LCMS containing 16-1 (analytical method 5, t)_R＝1.21min.，[M+H]⁺776.4) and 16-2 (analytical method 5, t)_R＝1.09min.，[M+H]⁺736.3) of 60/40. The product mixture was used in the next step without further purification.

Step 2.2- ((R) -4- (tert-butoxy) -2- ((R) -3- ((S) -3- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-oxobutyl) pyridine 1-oxide (16-3) and 2- ((R) -4- (tert-butoxy) -2- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2-carbonyl) - (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propanamide) -3-hydroxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-oxobutyl) pyridine 1-oxide (16-4)

A15(34mg, 0.12mmol) was added in one portion as a solution in DCM (4mL) by syringe to a 60/40 crude mixture of 16-1 and 16-2 (88mg, 0.12mmol) in a round bottom flask equipped with a magnetic stir bar. DIPEA (0.126mL, 0.12mmol) was then added in one portion via syringe followed by HATU (59mg, 0.16 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with DCM and saturated NH₄Cl (x2) and brine. Passing the organic phase over Na₂SO₄Drying, filtration and concentration in vacuo gave a pale yellow oil containing 16-3 as determined by LCMS (analytical method 5, t)_R＝1.23min.，[M+H]⁺1039.7) and 16-4 (analytical method 5, t)_R＝1.12min.，[M+H]⁺999.6). The crude mixture was used in the next step without further purification (assumed quantitative yield calculated for the reagents in the next step).

Step 3.2- ((R) -2- (carboxymethyl) -3- ((R) -3- ((S) -3- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -L-alanyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-oxapropyl) pyridine 1-oxide (16-5)

TFA (0.925mL, 12.00mmol) was added in one portion by syringe to the crude mixture containing 16-3 and 16-4(0.12mmol) in DCM (4mL) in a round bottom flask equipped with a magnetic stir bar. Will be described The mixture is obtained at room temperature under N₂Stirred under atmosphere for 2 hours and then concentrated in vacuo. The obtained residue was taken up in DCM and concentrated again in vacuo to give a crude yellow residue. The procedure was repeated (x2) to remove residual TFA. The crude product was taken up in DMSO (3mL), filtered, and subjected to reverse phase HPLC (30X100mm 5 μm column with 15% -40% MeCN: H₂O (with 5mM NH)₄OH), 2 × 1.5mL injection, 75mL/min) and freeze-drying the product containing fractions to give 13.2mg (11% yield) of 16-5 as a white powder. Analytical method 5, t_R＝0.80min.,[M+H]⁺＝983.6。

Step 4.2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine 1-oxide (Compound 66)

2, 6-lutidine (0.016mL, 0.13mmol) was added in one portion by syringe to 16-5(13.2mg, 0.01mmol) in DCM (13mL) in a round bottom flask equipped with a magnetic stir bar. HOAt (3.7mg, 0.03mmol) was then added followed by HATU (10.2mg, 0.03 mmol). The resulting mixture was heated to 40 ℃ overnight and then diluted with EtOAc. The organic phase was washed with saturated NaHCO ₃(x3) and brine, over Na₂SO₄Dried, filtered, and concentrated in vacuo. The crude material was transferred to a glass vial and taken up in DCM (0.5 mL). Addition of H₂O (0.3mL), followed by addition of TFA (0.2mL, 2.60mmol) at room temperature. The reaction mixture was stirred for 45 minutes, then partially concentrated in vacuo. The resulting residue was taken up in DMSO, filtered and subjected to reverse phase HPLC (30X100mm 5 μm column using 35% -60% MeCN: H₂O (with 5mM NH)₄OH), 1 × 1.5mL injection, 75mL/min) and freeze-drying the product containing fractions gave 0.6mg (5%) of compound 66 as a white solid. Analytical method 4, t_R＝1.63min.,[M+H]⁺＝925.5。

Example 8.36: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 4)

Step 1. tert-butyl (R) -4- ((R) -3-amino-3- (4-chlorobenzyl) piperidin-1-yl) -3- ((6-methylpyridin-2-yl) methyl) -4-oxobutyrate (17-1)

To a solution of a17(523mg, 1.68mmol) in anhydrous DMF (20mL) at 0 ℃ were added DIPEA (1.47mL, 8.40mmol) and B7(500mg, 1.68mmol), followed by HATU (703mg, 1.85mmol), and the resulting mixture was warmed to room temperature and stirred for 2 hours. EtOAc was added and the reaction mixture was washed with 5% NaHCO ₃Aqueous solution, saturated NaHCO₃The solution and brine washes. Passing the organic phase over Na₂SO₄Dried, filtered and concentrated. The crude material was purified by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH) and the product eluted at about 80% ACN) and gave 17-1(637mg, 78% yield) after freeze-drying of the pure fractions. This material contained the major impurities and was used in the next step without further purification. Analytical method 5, t_R＝1.12min.,[M+H]⁺＝486.3。

Step 2.(R) -4- ((R) -3- ((S) -2-amino-3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((6-methylpyridin-2-yl) methyl) -4-oxobutanoic acid (17-2)

To a mixture of 17-1(315mg, 0.65mmol) in dry DMF (5mL) was added a solution of (S) -2- ((tert-butoxycarbonyl) amino) -3-methoxypropionic acid (170mg, 0.78mmol), DIPEA (0.34mL, 1.94mmol), and HATU (296mg, 0.78mmol, 4mL) in DMF) and the resulting mixture was stirred at room temperature for 4 hours. EtOAc was added and the reaction mixture was washed with NaHCO₃The solution and brine washes. Passing the organic phase over Na₂SO₄Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 20% to 100% EtOAc in heptane, the product eluting at about 100% EtOAc) to afford, after concentration of the pure fractions, aTo 17-2 as a light brown oil (445mg, 85% yield). Analytical method 5, t _R＝0.60min.,[M+H]⁺＝531.4。

Step 3 methyl (R) -4- ((R) -3- ((S) -2-amino-3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((6-methylpyridin-2-yl) methyl) -4-oxobutyrate (17-3)

To a solution of 17-2(378mg, 0.55mmol) in anhydrous DCM (1mL) was added TFA (2.12mL, 27.5 mmol). The resulting mixture was stirred at room temperature for 2-3 hours, then concentrated to dryness under reduced pressure and dried under high vacuum to give 17-3(418mg, ca. quantitative yield). Analytical method 5, t_R＝0.96min.,[M+H]⁺＝545.3。

Step 4.(R) -4- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionamide) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- ((6-methylpyridin-2-yl) methyl) -4-oxobutyric acid (17-4)

Step 4-1: to a solution of 17-3(248mg, 0.45mmol) in anhydrous DMF (8mL) were added DE1(222mg, 0.50mmol), DIPEA (0.25mL, 1.43mmol) and HATU (208mg, 0.55mmol) and the resulting mixture was stirred at room temperature for 2-3 hours. EtOAc was added and the reaction mixture was washed with sodium carbonate solution and brine. Passing the organic phase over Na₂SO₄Dried, filtered and concentrated. The crude product was purified by reverse phase column chromatography (with 0-100% water/ACN, 0.1% NH)₄OH elution, product elution at about 90% ACN) to afford the desired product. The combined fractions were concentrated to remove excess ACN and extracted twice with EtOAc. Passing the organic phase over Na ₂SO₄Dried, filtered and concentrated to give methyl ester as a white foam (441mg, 37% yield).

Step 4-2: to the methyl ester from step 4-1 (164mg, 0.17mmol) in THF (6mL) and water (1.5mL) and cooled in an ice bath was added LiOH (1N, 0.25mL, 0.51 mmol). The resulting mixture was stirred at room temperature for 2 hours, then purified by addition of aqueous HCl (0.51mL, 0.507mmol) and NaHCO₃The solution was quenched (pH adjusted to 7-8). The reaction mixture was extracted with EtOAc (× 2) and the combined organic phases were dried over sodium sulfateFiltered, and concentrated to give 17-4 as a white gummy solid after drying (162mg, 87% yield). The product was used in the next step without purification. Analytical method 5, t_R＝1.79min.,[M+H]⁺＝955.7。

Step 5.(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 4)

To a solution of 17-4(141mg, 0.15mmol) in DCM (150mL) was added 2, 6-lutidine (0.5mL, 4.29mmol), HOAt (20.1mg, 0.15mmol), and HATU (224mg, 0.59 mmol). The resulting mixture was heated to reflux at 48 ℃ overnight, cooled to room temperature and concentrated to dryness. The resulting residue was purified by reverse phase column chromatography (with 0-100% water/pot (with 0.1% NH) ₄OH), then with 50-100% water/IPA (with 0.1% NH)₄OH) and the product eluted in 60% IPA) and concentration of the pure fractions to give the desired product. The product was again purified using basic HPLC to afford compound 4 as a white solid after freeze drying of the pure fractions (64mg, 45% yield). Analytical method 2, t_R＝2.83min.,[M+H]⁺＝937.3。

The compounds in table 25 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 4 in example 8.36.

Table 25:

example 8.37: synthesis of (3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 21)

Step 1.2- ((R) -2- ((R) -3- ((S) -2- ((tert-butoxycarbonyl) amino) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-methoxy-4-oxobutyl) pyridine 1-oxide (18-1)

Step 1-1: to a solution of 12-3(168mg, 0.38mmol) in anhydrous DMF (3mL) was added (S) -2- ((tert-butoxycarbonyl) amino) -3-methoxypropionic acid (99mg, 0.45mmol) and DIPEA (0.2mL, 1.14mmol), and the resulting mixture was stirred at room temperature. A solution of HATU (172mg, 0.45mmol) in DMF (3mL) was added and stirring was continued overnight. EtOAc was added and the reaction mixture was washed with sodium carbonate solution and twice with brine. Passing the organic phase over Na ₂SO₄Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 0-100% EtOAc/heptane, the product eluting at about 100% EtOAc as a broad peak, the remaining product eluting with 5% MeOH in EtOAc) to give an intermediate (233mg, 96%) which was used in the next step without further purification.

Step 1-2: to the product from step 1-1 (233mg, 0.36mmol) in dioxane (1mL) was added a solution of HCl in dioxane (5mL, 20.0mmol) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and dried under high vacuum to give 18-1(238mg, ca. quantitative yield) as a crude product, which was used in the next step without purification. Analytical method 7, t_R＝0.68min.,[M+H]⁺＝547.4。

Step 2.2- ((R) -2- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionamide) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-methoxy-4-oxobutyl) pyridine 1-oxide (18-2)

To a mixture of 18-1(238mg, 0.37mmol) in anhydrous DMF (6mL) were added DE1(195mg, 0.44mmol), DIPEA (0.32mL, 1.83mmol) and HATU (167mg, 0.44mmol) and the resulting mixture was stirred at room temperature for 2 h. EtOAc was added and the reaction mixture was washed with sodium carbonate solution, brine. Passing the organic phase over Na ₂SO₄Dried, filtered and concentrated. The crude product was purified by reverse phase column chromatography (using 10% -100% H)₂O/ACN (with 0.1% NH)₄OH) and the product eluted at about 75% ACN) to afford the desired product. The pure fractions were concentrated, extracted twice with EtOAc and over Na₂SO₄Drying, filtration and concentration gave 18-2(172mg, 48%) after drying under high vacuum. Analytical method 5, t_R＝1.08min.,[M+H]⁺＝971.4。

Step 3.2- ((R) -2- (carboxymethyl) -3- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propanamide) -3-methoxypropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-oxapropyl) pyridine 1-oxide (18-3)

To 18-2(172mg, 0.18mmol) in anhydrous THF (4mL) and water (1mL) and cooled in an ice bath was added LiOH (0.25mL, 0.50 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 4 hours. HCl (1N) was then added to adjust the pH to 7-8. The resulting mixture was then extracted with EtOAc (× 2) and DCM (× 2). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to afford 18-3 as a white foam after drying under high vacuum (162mg, 96% yield). Analytical method 5, t_R＝0.77min.,[M+H]⁺＝957.4。

Step 4.2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine 1-oxide (18-4)

To a mixture of 18-3(162mg, 0.17mmol) in DCM (100mL) was added HOAt (23mg, 0.17mmol), HATU (257mg, 0.68mmol), and 2, 6-lutidine (0.59mL, 5.07mmol) at room temperature. The resulting mixture was heated to reflux overnight (bath temperature 50 ℃), then cooled to room temperature, and concentrated to dryness under reduced pressure. The crude product was then taken up in EtOAc and washed with 5% NaHCO₃And (4) washing the solution. After decanting the aqueous phase, some product precipitated from the organic phase and was dissolved with ACN. The organic phase is concentrated to give a crude material which is passed through a reverse phase column (using 0)100% Water/ACN (with 0.1% NH)₄OH) and the product eluted at about 80% ACN). The pure fractions were concentrated and extracted with EtOAc (× 2). The organic phase was dried over sodium sulfate, filtered, and concentrated to afford 18-4(88mg, 55% yield) after high vacuum drying. Analytical method 5, t_R＝1.03min.,[M+H]⁺＝939.6。

Step 5.(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 21)

To a solution of 18-4(88mg, 0.09mmol) in THF (9mL) was added saturated NH ₄Cl (3.00mL), zinc powder (392mg, 5.99mmol), and citric acid (324mg, 1.68 mmol). The resulting mixture was stirred at room temperature for 1.5 hours and then passed

The pad is filtered. EtOAc was added and the mixture was washed with saturated NaHCO₃And (4) washing the solution. The phases were separated and the aqueous phase was back-extracted twice with EtOAc. The combined organic phases were concentrated. The crude product was purified by basic HPLC to afford compound 21(30mg, 34% yield) after freeze drying of the pure fractions. Analytical method 2, t_R＝2.76min.,[M+H]⁺＝923.6。

Example 8.38: synthesis of (3R,7S,10S,13R) -3- ((E) -but-2-en-1-yl) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 40)

Step 1.(R, E) -tert-butyl 3- ((R) -3- ((S) -3- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionyl) -2, 2-dimethyloxazolidine-4-carboxamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) hept-5-enoate (19-1)

To a solution of A23(106mg, 0.46mmol) in DMF (1.5mL) was added DIPEA (0.20mL, 1.16mmol) and HATU (184mg, 0.48 mmol). The resulting mixture was stirred at room temperature for 5 minutes, then added to a solution of 1-4(300mg, 0.39mmol) in DMF (2 mL). The reaction mixture was stirred for 2 hours, then quenched with 5% sodium bicarbonate solution and extracted with EtOAc. The organic phase was washed with 5% sodium bicarbonate and brine, respectively, dried over sodium sulfate, filtered and concentrated to give 19-1 as a foam after drying under high vacuum (390mg, assuming quantitative yield). This material was used in the next step without purification. Analytical method 5, t _R＝1.41min.,[M+H]⁺＝986.8。

Step 2.(R, E) -3- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionamide) -3-hydroxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) hept-5-enoic acid (19-2)

To a solution of 19-1(390mg, 0.40mmol) in DCM (3mL) and cooled in an ice bath was added TFA (3mL, 38.9mmol) dropwise. The cooling bath was then removed and the resulting mixture was stirred at room temperature for 3 hours. Water and ACN (1:1 ratio, 4mL) were added and stirring continued at room temperature for an additional 2 hours. The reaction mixture was concentrated and the residue obtained was taken up in DCM with stirring and sodium carbonate was added to adjust the pH of the aqueous phase slightly basic. The organic phase was then collected and the aqueous phase was back-extracted again with DCM. The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give 19-2 as a pale yellow foam (333mg, 95% yield). The product was used in the next step without purification. Analytical method 5, t_R＝0.81min.,[M+H]⁺＝890.3。

Step 3.(3R,7S,10S,13R) -3- ((E) -but-2-en-1-yl) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 40)

To a solution of 19-2(278mg, 0.31mmol) in DCM (140mL) was added HOAt (42.5mg, 0.31mmol), HATU (475mg, 1.25mmol), and 2, 6-lutidine (0.8mL, 6.87 mmol). Will be describedThe resulting mixture was heated to reflux overnight (bath temperature 50 ℃) then cooled to room temperature and washed with 5% aqueous sodium bicarbonate. The organic phase was separated and concentrated to dryness to give the crude product, which was purified by basic HPLC (water/ACN with ammonium hydroxide modifier) to afford compound 40 as a white powder after freeze drying of the pure fractions (18mg, 6.4% yield). Analytical method 2, t_R＝2.92min.,[M+H]⁺＝872.2。

The compounds in table 26 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 40 in example 8.38.

Table 26:

example 8.38: synthesis of (3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((cyclobutylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 45)

Step 1.(S) -methyl 3- ((R) -3- ((S) -2-amino-3-methoxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoate (20-1)

Step 1-1: to a solution of (S) -2- ((tert-butoxycarbonyl) amino) -3-methoxypropionic acid (1.30g, 5.92mmol) in DMF (25mL) was added HATU (2.47g, 6.51mmol) and DIPEA (3.10mL, 17.7 mmol). The resulting mixture was stirred for 2 minutes, then a solution of 7-2(2.49g, 5.92mmol) in DMF (5mL) was added. The reaction mixture was stirred at room temperature overnight to complete the reaction. EtOAc was added and the mixture was washed with 5% aqueous sodium bicarbonate solution (x2) then brine. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the intermediate product as a dark brown oil after drying (3.9g, ca. quantitative yield). The material was used in the next step without further purification.

Step 1-2: to a solution of the product of step 1-1 (1.7g, 2.73mmol) in DCM (5mL) was added TFA (4.21mL, 54.7mmol) dropwise at room temperature. The resulting mixture was stirred for 2 hours and then concentrated. The residue obtained was taken up in DCM and washed with saturated sodium bicarbonate solution. The organic phases were collected, dried over sodium sulfate, filtered, and concentrated to give 20-1 as a crude red foam after drying (1g, 70% yield). This material was used in the next step without purification. Analytical method 2, t_R＝2.16min.,[M+H]⁺＝522.3

Step 2.(S) -methyl 3- ((R) -3- ((S) -2- ((S) -2-aminopropionamide) -3-methoxypropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluorovalerate (20-2)

Step 2-1: to a solution of Boc-Ala-OH (0.36g, 1.92mmol) in DMF (10mL) was added HATU (0.80g, 2.11mmol) and DIPEA (1.0mL, 5.75 mmol). The resulting mixture was stirred for 2 minutes, then a solution of 20-1(1g, 1.92mmol) in DMF (5mL) was added. The reaction mixture was stirred at room temperature for 1 hour. EtOAc was added and the mixture was washed twice with 5% sodium bicarbonate solution and then with brine. The organic phase was dried over sodium sulfate, filtered and concentrated to give a dark brown oil. The crude material was purified by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH modifier) eluted, the product eluted at about 80% ACN). The reaction was repeated on the same scale and combined to give intermediate (1.3g, 99% yield) after concentration of all pure fractions.

Step 2-2: to a solution of the product of step 2-1 (1.3g, 3.03mmol) in DCM (3mL) was added TFA (3mL, 40.2mmol) dropwise. The resulting mixture was then stirred at room temperature overnight. MeOH was then added, and the mixture was stirred for 1 hour, then concentrated. The resulting residue was taken up in EtOAc and washed with 5% sodium bicarbonate. The aqueous phase was back-extracted again with EtOAc, and the combined organic phases were dried over sodium sulfate, filtered, and concentrated to give example 20-2 as a pale yellow foam (1.09g, 98% yield). The product was used in the next step without purification. Analytical method 5, t _R＝0.97min.,[M+H]⁺＝593.3

Step 3.(S) -methyl 3- ((R) -3- ((S) -2- ((S) -2- ((2- (4- (2- (((tert-butoxycarbonyl) (cyclobutyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) amino) propanamide) -3-methoxypropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoate (20-3)

To a round bottom flask containing 20-2(265mg, 0.45mmol) and E18(230mg, 0.45mmol) were added DCM (10ml) and acetic acid (0.10ml, 1.79mmol), and the resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (474mg, 2.24mmol) was added and stirring continued at room temperature overnight. The reaction mixture was then concentrated and the obtained residue was taken up in EtOAc and washed with half-saturated sodium carbonate solution (twice) and brine. Passing the organic phase over Na₂SO₄Drying, filtration and concentration to dryness gave 20-3 as an oil (488mg, assuming quantitative yield). This material was used in the next step without purification. Analytical method 5, t_R＝1.46min.,[M+H]⁺＝1090.4。

Step 4.(S) -3- ((R) -3- ((S) -2- ((S) -2- ((2- (4- (2- (((tert-butoxycarbonyl) (cyclobutyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) amino) propanamide) -3-methoxypropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (20-4)

To a round bottom flask containing 20-3(488mg, 0.45mmol) in dioxane (8mL) and water (2mL) and cooled in an ice bath was added dropwise sodium hydroxide (1M, 1.79mL, 1.79 mmol). The cooling bath was removed and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then cooled with an ice bath and quenched with a solution of HCl (1M, 1.34ml, 1.34mmol) in water (2 ml). The mixture was stirred at room temperature for 15 minutes and then lyophilized to give a crude solid. The solid was absorbed in ACN and purified by reverse phase column chromatography (with 0-100% water/ACN (with 0.1% NH)₄OH as modifier) and the product eluted at about 50% ACN). The pure fractions were concentrated to give a white slurry and extracted with 10% MeOH in EtOAc (× 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to give 20-4 as a white solid (200mg, 42% yield). Analytical method 5, t_R＝1.01min.,[M+H]⁺＝1076.0。

Step 5.(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((cyclobutylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 45)

Step 5-1: to a solution of 20-4(200mg, 0.19mmol) in DCM (250mL) was added 2, 6-lutidine (0.5mL, 4.29mmol), HOAt (25.3mg, 0.19mmol), and HATU (282mg, 0.74 mmol). The resulting mixture was heated in a 45 ℃ heating bath overnight, then cooled to room temperature, filtered and concentrated. The obtained residue was taken up in EtOAc and taken up with saturated NaHCO₃And a brine wash. Passing the organic phase over Na₂SO₄Dried, filtered and concentrated to give the product as an oil (197mg, ca. quantitative yield). This material was used directly in the next step without purification.

Step 5-2: to a solution of the product of step 5-1 (197mg, 0.19mmol) in DCM (2mL) and cooled to 0 ℃ in an ice bath was added TFA (2mL, 26.0mmol) dropwise and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated and the resulting residue was taken up in EtOAc. The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by basic HPLC (water/ACN, ammonium hydroxide as modifier) to afford compound 45 as a white solid after freeze drying of the pure fractions (42.6mg, 23% yield). Analytical method 2, t_R＝3.08min.,[M+H]⁺＝958.3。

Example 8.39: synthesis of (3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 27)

Step 1. Tert-butyl ((S) -1- (((S) -1- (((R) -3- (4-chlorobenzyl) -1- ((4-nitrophenyl) sulfonyl) piperidin-3-yl) (methyl) amino) -3-hydroxy-1-oxoprop-2-yl) amino) -1-oxoprop-2-yl) carbamate (21-2)

To a solution of (S) -2- ((tert-butoxycarbonyl) amino) propionic acid (0.31g, 1.61mmol) in DMF (6mL) was added DIPEA (0.85mL, 4.84mmol) and TBTU (0.52g, 1.61 mmol). The resulting mixture was stirred at room temperature for 2 minutes. Then added to a solution of 13-3(0.82g, 1.61mmol) in DCM (6mL) containing DIPEA (0.84mL, 4.84mmol) and cooled in a dry ice bath. The reaction mixture was gradually warmed to room temperature, stirred for 30 minutes, and then added to saturated NaHCO₃And water to form a two-phase mixture. The organic phase was separated and the aqueous portion was back-extracted twice with DCM. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to give 21-2 as crude product (1.1g, assuming quantitative yield). The crude product was used without further purification. Analytical method 5, t_R＝1.10min.,[M+H]⁺＝682.2

Step 2. Tert-butyl ((S) -1- (((S) -1- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) (methyl) amino) -3-hydroxy-1-oxoprop-2-yl) amino) -1-oxoprop-2-yl) carbamate (21-3)

To a solution of 21-2(1.09g, 1.6mmol) in MeOH (75mL) at room temperature was added thioglycolic acid (0.45mL, 6.40mmol) and Cs₂CO₃(3.65g, 11.2 mmol). The resulting mixture was stirred at room temperature for 40 min (LCMS observed formation of isomeric product), then poured into 200mL of cold water and extracted with 2x80mL EtOAc (brine added to aid partitioning). The combined organic phases were washed with 5% NaHCO₃The solution was washed twice, dried over sodium sulfate, filtered, and concentrated to give 21-2(594mg, 75% yield) as a crude yellow foam after drying under high vacuum. The product was used in the next step without purification. Analytical method 5, t_R＝0.98min.,[M+H]⁺＝497.4。

Step 3. tert-butyl (R) -3-benzyl-4- ((R) -3- ((S) -2- ((S) -2- ((tert-butoxycarbonyl) amino) propanamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutanoate (21-4)

To a solution of A1(190mg, 0.72mmol) in ACN (8mL) was added DIPEA (0.63mL, 3.59mmol) and HATU (273mg, 0.72 mmol). The resulting mixture was stirred at room temperature for 5 minutes. Then added to a solution of 21-3(594mg, 1.19mmol) in ACN (8.00mL) at 0 ℃. The reaction mixture was stirred at room temperature for 30 minutes, then concentrated. The residue was purified by flash column chromatography on silica gel (eluting with 0-100% EtOAc/heptane, product eluting at about 80% EtOAc) to give 21-4(430mg, 80% yield) after concentration of the clean fractions. Analytical method 5, t _R＝1.28min.,[M+H]⁺＝743.6。

Step 4. tert-butyl (R) -3-benzyl-4- ((R) -3- ((S) -2- ((S) -2- ((tert-butoxycarbonyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutanoate (21-5)

To a solution of 21-4(200mg, 0.270mmol) in ACN (4mL) was added Ag₂O (312mg, 1.34mmol) and MeI (0.168mL, 2.69 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere in the dark overnight to complete the reaction. Then the reaction mixture is passed through

Pad filtration and concentration gave 21-5 (approx. quantitative yield). The product was used in the next step without purification. Analytical method 5, t_R＝1.34min.,[M+H]⁺＝757.6。

Step 5.(R) -4- ((R) -3- ((S) -2- ((S) -2-aminopropionamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutyric acid (21-6)

To a solution of 21-5(0.401g, 0.53mmol) in DCM (2mL) was added TFA (4.08mL, 53.0mmol) dropwise. The resulting mixture was stirred at room temperature for 2 hours, then concentrated. The residue obtained was taken up in toluene and concentrated again (repeated 3 times in total to ensure removal of TFA) to afford 21-6(156mg, assumed quantitative yield) after drying under high vacuum. The solid was used in the next step without purification. Analytical method 5, t_R＝0.64min.,[M+H]⁺＝601.5。

Step 6.(R) -3-benzyl-4- ((R) -3- ((S) -2- ((S) -2- ((4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) amino) propionamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutyric acid (21-7)

To a solution of 21-6(156mg, 0.26mmol) in anhydrous DCM (5mL) were added E14(96mg, 0.26mmol) and acetic acid (0.02mL, 0.39 mmol). The resulting mixture was stirred at room temperature overnight, then sodium triacetoxyborohydride (220mg, 1.04mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours, then quenched with water and MeOH and concentrated. The crude residue was purified by reverse phase column chromatography eluting with 20% to 50% ACN water (with 0.1% TFA) to afford examples 21-7 as a white solid after freeze drying of the pure fractions (130mg, 52% yield). Analytical method 5, t_R＝0.80min.,[M+H]⁺＝955.6。

Step 7.(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 27)

To a stirred mixture of 21-7(130mg, 0.14mmol), HATU (207mg, 0.54mmol) and HOAt (27.8mg, 0.20mmol) in DCM (130mL) was added 2, 6-lutidine (0.32mL, 2.72mmol) at room temperature. The resulting mixture was heated to 40 ℃ for 4 hours, then cooled to room temperature and washed twice with water. The organic phase was concentrated to give the crude product, which was purified by basic HPLC (with water/ACN (0.1% NH) ₄OH) and the product eluted at about 75% ACN) and compound 27 was obtained as a white solid after freeze drying of the pure fractions (25mg, 19% yield). Analytical method 2, t_R＝3.12min.,[M+H]⁺＝937.6。

The compounds in table 27 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 27 in example 8.39.

Table 27:

example 8.40: synthesis of (3R,7S,10S,13R) -3-benzyl-10- (((tert-butyldimethylsilyl) oxy) methyl) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 71)

Step 1.(R) -4- ((R) -3- ((S) -2- ((S) -2-aminopropionamide) -3-hydroxy-N-methylpropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutyric acid (23-2)

To a solution of 21-4(2.45g, 3.30mmol) in anhydrous EtOAc (30ml) was added TFA (229ml, 296mmol) dropwise. The resulting mixture was stirred at room temperature for 1 hour, then concentrated. The residue obtained was dried thoroughly under high vacuum to afford 23-2(1.9g, approx. quantitative yield). The product was used in the next step without purification. Analytical method 5, t _R＝0.62min.,[M+H]⁺＝587.3。

Step 2.(R) -3-benzyl-4- ((R) -3- ((S) -3- ((tert-butyldimethylsilyl) oxy) -2- ((S) -2- ((4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) amino) propionamide) -N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutyric acid (23-3)

Step 2-1: to a solution of 23-2(82mg, 0.14mmol) in dry DCM (6ml) were added E14(40mg, 0.11mmol) and acetic acid (0.025ml, 0.43 mmol). DIPEA (0.1mL) was then added to homogenize the mixture, and the resulting solution was stirred at room temperature for 2 hours. Adding Na (AcO) at a time₃BH (114mg, 0.54mmol) and stirring was continued for 1.5 h. The reaction mixture was quenched by the addition of water and then concentrated. The crude product was purified by reverse phase column chromatography (with 30% -50% ACN/water (with 0.1% NH)₄OH) elution) pureAfter purification and concentration of the clean fractions, the intermediate product was obtained (50mg, 48% yield).

Step 2-2: to a solution of the intermediate of step 2-1 (50mg, 0.05mmol) and imidazole (72.3mg, 1.06mmol) in DMF (2mL) was added TBDMS (60mg, 0.40 mmol). The resulting mixture was stirred at room temperature for 16 hours. Addition of half-saturated NaHCO₃Solution (10mL) and then solid K was added₂CO₃(50mg) and stirring was continued at room temperature for 1 hour. The reaction mixture was then extracted with EtOAc and the organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase column chromatography (with 0-100% ACN/water (with 0.1% NH) ₄OH) elution) and freeze dried the clean fractions to give 23-2 as a white solid (35mg, 24% yield). Analytical method 5, t_R＝1.03min.,[[M+H]⁺/2]⁺＝433.5。

Step 3.(3R,7S,10S,13R) -3-benzyl-10- (((tert-butyldimethylsilyl) oxy) methyl) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 71)

Step 3-1: to a round bottom flask containing 23-3(35mg, 0.03mmol), HATU (50.4mg, 0.13mmol) and HOAt (6.8mg, 0.05mmol) was added DCM (35mL) and the resulting mixture was stirred at room temperature for several minutes. 2, 6-lutidine (0.08mL, 0.66mmol) was added and stirring was continued at 40 ℃ for 16 h. The reaction mixture was cooled to room temperature, and water (30ml) was added. The organic phase was drained and concentrated. The residue obtained was taken up in 100mL of EtOAc and the organic phase was washed with water (50mL) and brine (50mL) over Na₂SO₄Drying, filtering and concentrating. The crude residue was dried under high vacuum to give the crude cyclized product.

Step 3-1: the product of step 3-1 was taken up directly in THF (3mL) and TBAF (1N in THF, 0.28mL, 0.28mmol) was added. The resulting mixture was stirred at room temperature for 4 hours, then concentrated. The crude residue was purified by reverse phase column chromatography eluting with 50% to 90% ACN/water (with 0.1% TFA) to afford the desired fractions after freeze drying And (3) obtaining the product. The product was again passed through basic HPLC (with ACN/water (with 0.1% NH)₄OH) elution) and freeze-dried the pure fractions to give compound 71 as a white powder (9mg, 29% yield). Analytical method 2, t_R＝2.89min.,[M+H]⁺＝923.5。

The compounds in table 28 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 71 in example 8.40.

Table 28:

example 8.41: synthesis of (2S,5S,8R,12S) -8- (4-chlorobenzyl) -12- ((S) -2, 3-dihydro-1H-inden-1-yl) -1- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-ethylbenzyl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone (Compound 119)

Step 1.(S) -4- (((R) -2- ((tert-butoxycarbonyl) (methyl) amino) -3- (4-chlorophenyl) propyl) (methyl) amino) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid (24-2)

To a mixture of a4(2.05g, 5.37mmol) and HATU (2.24g, 5.90mmol) suspended in DCM (30mL) was added DIPEA (3.75mL, 21.5mmol) and the resulting mixture was stirred at rt for 30 min. A solution of B1(2.8g, 8.85mmol) in DCM (30mL) was added and stirring continued at room temperature for 16 h. The reaction mixture was then concentrated and the residue was taken up in EtOAc (50mL) and 5% NaHCO ₃The aqueous solution (10mL) was partitioned. The organic phase was washed with 5% NaHCO₃Aqueous (3 × 10mL) and brine (10mL) were washed over Na₂SO₄Drying, filtration and concentration gave 24-2 as a beige oil (3.1g, assuming quantitative yield). The crude product was used in the next step without purification. Analytical method 5, t_R＝1.48min.,MS[M+H]⁺＝585.5。

Step 2 (S) -4- (((R) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) (methyl) amino) -3- (4-chlorophenyl) propyl) (methyl) amino) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoic acid (24-3)

To a round bottom flask containing 24-2(3.10g, 5.30mmol) was added TFA (20.4mL, 265 mmol). The resulting solution was stirred at room temperature for 1 hour, then concentrated to dryness in vacuo. The residue obtained was dissolved in dioxane (50mL) and 0.5M Na was added₂CO₃Aqueous solution (74.2mL, 37.1mmol) and Fmoc-OSu (4.82g, 14.3mmol in 5mL dioxane). The resulting mixture was stirred at room temperature for 16 hours, then quenched with 1M aqueous HCl (40 mL). The reaction mixture was then concentrated and the residue was taken up in EtOAc (200 mL). The phases were separated. The organic phase was washed with brine (50mL) and Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with 30% to 90% heptane EtOAc (with 1% acetic acid) to give the desired product as an oily residue after concentration of the pure fractions. The product was then taken up in a mixture of ACN (10mL) and water (3mL) and lyophilized to give 24-3 as a white solid (3.23g, 66% yield). Analytical method 5, t _R＝0.86min.,[M+H]⁺＝650.7。

Step 3 resin-Supported (3S) - (2-chlorophenyl) (phenyl) (p-tolyl) methyl-4- (((R) -3- (4-chlorophenyl) -2- (methylamino) propyl) (methyl) amino) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -4-oxobutanoate (24-4)

Step 3.1: the 2-chlorotrityl chloride resin (7.75g, 12.4mmol) was first washed well with DCM. A solution of 24-3(3.2g, 4.96mmol) in DCM (30mL) containing DIEA (4.33mL, 24.8mmol) was then added to the resin. The resulting slurry was shaken at room temperature for 3.5 hours, and then the solution was drained. The resulting resin was washed sequentially with a solution of DCM/MeOH/DIPEA (17:2:1, 30mL), 30mL DCM, and finally 30mL DMA.

Step 3.2: fmoc-removal to the resin of step 3.1 was added a solution of 4-methylpiperidine in DMF (25%, 40mL) and the resulting suspension was shaken at room temperature for 90 minutes. The slurry was then drained and the process repeated twice, washing the resin with more 4-methylpiperidine/DMF solution. The resin was then washed with DMF (3x50mL) and then DCM (3x50mL) and dried in vacuo to give the corresponding resin-supported product 24-4, which was used in the next step without further purification.

Step 4 resin-Supported (6S,9R,13S) - (2-chlorophenyl) (phenyl) (p-tolyl) methyl 6-amino-9- (4-chlorobenzyl) -13- ((S) -2, 3-dihydro-1H-inden-1-yl) -2,2,3,3,8, 11-hexamethyl-7, 12-dioxo-4-oxa-8, 11-diaza-3-silapentadecane-15-oate (24-5)

Step 4-1: to resin 24-4(4.96mmol) was added a solution of Fmoc-Ser (BSI) -OH (3.29g, 7.44mmol), HATU (2.83g, 7.44mmol), DIPEA (2.60mL, 14.88mmol) in DMF (60 mL). The resulting slurry was then shaken overnight at room temperature and then drained. The resin was washed successively with DMF (6X50mL) and DCM (6X50 mL). The washing process was repeated again to give the resin intermediate, which was used directly in the next step.

Step 4-2: fmoc-removal to the resin of step 4-1 was added a solution of 4-methylpiperidine in DMF (25%, 50mL) and the resulting suspension was shaken at room temperature for 1.5 hours. The slurry was then drained and the process repeated with another 4-methylpiperidine/DMF solution for 1 hour. The resin was then washed with DMF (3x50mL), DCM (4x50mL) and dried in vacuo to give 24-5. The resin was used in the next step without further purification. MS [ M + H ]]⁺630.2 (a small amount of resin was cleaved for analytical purposes).

Step 5 (6S,9R,13S) -6- ((S) -2-aminopropionamide) -9- (4-chlorobenzyl) -13- ((S) -2, 3-dihydro-1H-inden-1-yl) -2,2,3,3,8, 11-hexamethyl-7, 12-dioxo-4-oxa-8, 11-diaza-3-silapentadecane-15-oic acid (24-6)

Step 5-1: Fmoc-Ala-OH coupling-to a mixture of Fmoc-L-Ala-OH (2.32g, 7.44mmol), HATU (2.83g, 7.44mmol) in DMF (70mL) was added DIPEA (2.6mL, 14.9 mmol). The resulting solution was stirred for several minutes and then added to a shaking funnel containing resin 24-5(4.57g, 4.96 mmol). The suspension was shaken at room temperature for 17 hours, then drained and washed with DMF (3 × 50 mL). The resulting resin was used directly in the next step.

Step 5-2: fmoc-removal to the resin of step 5-1 was added a solution of 4-methylpiperidine in DMF (25%, 40mL) and the suspension was shaken at room temperature for 10 min. The slurry was then drained and the process repeated twice with more 4-methylpiperidine solution. The remaining resin was then washed with DMF (3x50mL) and DCM (3x50mL) to give the corresponding resin-supported product, which was used in the next step without further purification.

Step 5-3: from resin cleavage-to the resin of step 5-2 was added a solution of hexafluoro-2-propanol in DCM (25%, 40 mL). The resulting suspension was shaken at room temperature for 15 minutes, then the solution was drained and the filtrate was collected. This procedure was repeated two more times with hexafluoro-2-propanol solution. The remaining resin was washed with DCM (2 × 40 mL). All organic phases were combined and concentrated to dryness. The crude material was purified by reverse phase column chromatography (using 30% -50% ACN/water (with 0.1% NH)₄OH) elution) and concentration of the clean fractions gave 24-6 as an orange oil (1.75g, 2.49mmol, 50.3% yield). Analytical method 2, t_R＝2.11min.,[M+H]⁺＝701.3。

Step 6.(3S,6S,9R,13S) -6- (((tert-butyldimethylsilyl) oxy) methyl) -9- (4-chlorobenzyl) -13- ((S) -2, 3-dihydro-1H-inden-1-yl) -1- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-ethylphenyl) -3,8, 11-trimethyl-4, 7, 12-trioxa-2, 5,8, 11-tetraazapentadecane-15-oic acid (24-7)

To a round bottom flask containing 24-6(578mg, 0.82mmol) was added a solution of E43(300mg, 0.82mmol) in 60mL anhydrous DCM. The resulting mixture was stirred at room temperature overnight and then concentrated. The residue obtained was then taken up in MeOH (60mL) and the cloudy mixture was stirred while cooling in an ice bath. Sodium borohydride (94mg, 2.47mmol) was then added slowly in portions and stirring was continued for 30 minutes while cooling in an ice bath. The reaction mixture was quenched with water (1mL), treated with acetic acid (0.07mL, 1.24mmol) at room temperature for 30 min, and thenAnd then concentrated. The crude product was purified by reverse phase column chromatography (with 0-100% ACN/water (with 0.1% NH)₄OH) elution) and freeze drying the pure fractions to give the desired product. The product was then taken up in EtOAc (500mL) and the organic phase was washed with water (150 mL). The organic phase was separated and the aqueous phase back-extracted with more EtOAc (200 mL). The combined organic phases were dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to give 24-7(0.70g, 81% yield). Analytical method 5, t_R＝1.08min.,[M+H]⁺＝1049.8

Step 7.(2S,5S,8R,12S) -8- (4-chlorobenzyl) -12- ((S) -2, 3-dihydro-1H-inden-1-yl) -1- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-ethylbenzyl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone (Compound 119)

Step 7.1: to a round bottom flask containing 24-7(0.75g, 0.72mmol), HATU (1.09g, 2.86mmol) and HOAt (0.15g, 1.07mmol) was added anhydrous DCM (715mL) and the resulting mixture was stirred at room temperature for several minutes and 2, 6-lutidine (1.67mL, 14.3mmol) was added. The reaction was heated to 39 ℃ for 5 hours and then cooled to room temperature. Water (50mL) was added to give a biphasic mixture. The organic phase was separated, washed with water and concentrated. The residue was dried under high vacuum to give the intermediate cyclized intermediate, which was used directly in the next step without purification.

Step 7.2: to a round bottom flask containing the intermediate from step 7.1 in THF (20mL) was added TBAF (1N in THF, 3.0mL, 3.0mmol) and the resulting mixture was stirred at rt for 16 h. Water (20mL) was added followed by EtOAc (100 mL). The organic phase was separated and concentrated to dryness. The resulting residue was purified by reverse phase column chromatography (using 50% -80% isopropanol/water (with 0.1% NH)₄OH) elution) and freeze-dried the pure fractions to give compound 119 as a white powder (373mg, 55% yield). Analytical method 2, t_R＝3.01min.,[M+H]⁺During the purification process, isomer compounds 121(15mg) and 118(28mg) were also obtained.

The compounds in table 29 were synthesized starting from a4 and intermediate N according to the procedure described for compound 119 in example 8.41.

Table 29:

example 8.42: synthesis of (3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butyl (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 137)

To a reaction vial containing paraformaldehyde (566mg, 18.8mmol) was added anhydrous MeOH (22 mL). The resulting slurry was sonicated for several minutes under ultrasound and then vigorously stirred at room temperature for 1 hour. Then compound 138(181mg, 0.19mmol) was added and stirring continued at room temperature for 1 hour. Sodium triacetoxyborohydride (798mg, 3.77mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Additional sodium triacetoxyborohydride (up to 40 equivalents) was added until complete consumption of the starting material was observed. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure (30 ℃ bath) to give a clear oil. The material was taken up in DCM and washed with saturated sodium bicarbonate solution. The weakly basic aqueous portion (pH about 8) was washed with DCM (× 2) and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (eluting with DCM/MeOH, the product at about 10%) and the pure fractions were concentrated to give a white film. The resulting material was taken up in a 1:1 mixture of ACN and water and lyophilized to give compound 137 as a white powder (173mg, 89% yield). Analytical method 3, t _R＝1.17min.,[M+H]⁺＝974.4。

The compounds in table 30 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 137 in example 8.42.

Table 30:

example 8.43: synthesis of (3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 136)

Step 1. tert-butyl (R) -3- ((S) -2- ((S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (26-1)

To a mixture of Fmoc-L-alanine (3.03g, 9.74mmol) and TBTU (3.13g, 9.74mmol) in ACN (100mL) was added DIPEA (4.86mL, 27.8 mmol). The resulting mixture was stirred at room temperature for 5 minutes. A clear solution was obtained. Intermediate F (5.1g, 9.27mmol) was then added and stirring continued at room temperature for 1 hour. The reaction mixture was treated with water (30mL) and then concentrated to remove excess organic solvent. The resulting residue was extracted with DCM (2 × 100mL) and the organic phase was washed successively with saturated NaHCO3, water and brine, over sulfuric acid Sodium was dried, filtered, and concentrated to give 26-1 as crude product (6.95g, assuming quantitative yield), which was used directly in the next step without purification. Analytical method 3, t_R＝1.34min.,[M+H]⁺-100＝633.4。

Step 2. (9H-fluoren-9-yl) methyl ((S) -1- (((S) -1- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) (methyl) amino) -3-methoxy-1-oxoprop-2-yl) amino) -1-oxoprop-2-yl) carbamate (26-2)

To a solution of 26-1(6.95g, 9.48mmol) in anhydrous MeOH (100mL) was added dropwise a cold solution of HCl (4N in dioxane (71.1mL, 284 mmol)) at 0 ℃. The cooling bath was then removed and the resulting mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue obtained was dried under high vacuum to give 26-2(6.35g, ca. quantitative yield), which was used in the next step without purification. Analytical method 3, t_R＝1.22min.,[M+H]⁺＝633.8。

Step 3 (S) -tert-butyl 3- ((R) -3- ((S) -2- ((S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluorovalerate (26-3)

To a mixture of A14(2.55g, 9.95mmol), HATU (3.78g, 9.95mmol) in ACN (100mL) was added DIPEA (8.28mL, 47.4 mmol). The resulting mixture was stirred at room temperature for several minutes, then added to a cooled solution of 26-2(6.35g, 9.48mmol) in ACN (100mL) cooled in an ice bath. The cooling bath was removed and stirring was continued at room temperature for 60 minutes. The reaction mixture was then treated with 15mL of water and concentrated. The residue was extracted twice with EtOAc (2 × 100 mL). The organic phase is successively treated with saturated NaHCO ₃Water and brine, over Na₂SO₄Drying, filtration and concentration gave 26-3(8.26g, approx. quantitative yield). This material was used in the next step without purification. Analytical method 3, t_R＝1.40min.,[M+H]⁺＝871.3。

Step 4.(S) -3- ((R) -3- ((S) -2- ((S) -2-aminopropionamide) -3-methoxy-N-methylpropionamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (26-4)

Step 4.1: to a solution of 26-3(8.26g,9.48mmol) in DCM (100mL) was added TFA (21.91mL, 284mmol) slowly. The resulting mixture was stirred at room temperature for 2 hours, then saturated NaHCO was added with stirring₃Solution to obtain a two-phase mixture. The organic phase was separated and the aqueous phase was back-extracted with more DCM. The combined organic phases are passed over Na₂SO₄Dried, filtered and concentrated to give an intermediate product. This material was used directly in the next step without further purification. MS [ M + H ]]⁺＝815.4

Step 4.2: the product from step 4.1 in DCM (100mL) was treated with 4-methylpiperidine (4.49mL, 37.9mmol) at 0 ℃. The cooling bath was removed and the resulting mixture was stirred at room temperature for 30 minutes. Then another portion of 4-methylpiperidine (4.49mL, 37.9mmol) was added and stirring was continued at room temperature for 60 minutes. The reaction mixture was then concentrated and the residue was purified by reverse phase column chromatography (with 0-100% ACN/water (with 0.1% NH) ₄OH) elution) and freeze-drying of the pure fractions gave 26-4(2.37g, 40.9% yield). Analytical method 2, t_R＝1.19min.,[M+H]⁺＝593.5。

Step 5.(S) -3- ((R) -3- ((S) -2- ((S) -2- ((2- (4- (2- (((tert-butoxycarbonyl) (tert-butyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (26-5)

To a mixture of 26-4(304mg, 0.51mmol) and E17(270mg, 0.52mmol) in DCM (8mL) was treated with AcOH (0.09mL, 1.57mmol) and the resulting solution was stirred at room temperature for 1 hour. Add NaBH (OAc) in one portion₃Sodium (444mg, 2.09mmol) and stirring was continued for 1.5 h. EtOAc (100mL) was added and the organic phase was washed with 5% NaHCO₃The solution (50mL) was washed with Na₂SO₄Dried, filtered and concentrated. The crude oily product was purified by reverse phase column chromatography (with 0-100% ACN/water (with 0.1% NH)₄OH) elution) and freeze-drying the pure fractions gave 26-5(373mg, 0.321mmol, 61% yield) as a white powder. Analytical method 5, t_R＝1.02min.,[M+H]⁺＝1092.1。

Step 6. tert-butyl-tert-butyl ((5- (4- (5-chloro-2- (((3S,7S,10S,13R) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-2, 5,8, 11-tetraoxo-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecan-6-yl) methyl) -3-fluorophenoxy) phenyl) -1-methyl-1H-imidazol-2-yl) methyl) carbamate (26-6)

To a solution of 26-5(373mg, 0.34mmol) in anhydrous DCM (150mL) were added 2, 6-lutidine (1.19mL, 10.2mmol), HOAt (46.4mg, 0.34mmol), and HATU (519mg, 1.36 mmol). The resulting mixture was heated to reflux in a heating bath at 45 ℃ overnight. The reaction mixture was cooled to room temperature and then concentrated. The residue obtained was taken up in EtOAc (100mL) and 5% NaHCO₃The aqueous solution (50mL) was partitioned. The separated organic phase was washed with 5% NaHCO₃Aqueous (3 × 50mL) and brine (50mL) were washed over Na₂SO₄Drying, filtration and concentration gave 26-6 as a crude oil (368mg, assuming quantitative yield). The product was used in the next step without further purification. Analytical method 5, t_R＝1.45min.,[M+H]⁺＝1074.7。

Step 7.(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (compound 136)

To a pre-cooled solution of 26-6(368mg, 0.34mmol) in anhydrous DCM (20mL) was slowly added TFA (3.95mL, 51.3mmol) dropwise. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 hour. Additional TFA was added and stirring was continued for 1.5 hours. The reaction mixture was added carefully to saturated NaHCO with stirring at room temperature ₃In solution (100mL) and then extracted twice with EtOAc (2 × 100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting oil was purified by reverse phase column chromatography eluting with 0-100% ACN/water (with 0.1% TFA) to afford the desired product as a TFA salt. The product was then taken up in EtOAc and NaHCO₃And stirred at room temperature for several minutes. The organic phase was separated and concentrated to give the desired product as the free base. The material was purified by basic HPLC (with 0-100% ACN/water)(with 0.1% NH)₄OH) and then purified by flash column chromatography on silica gel (eluting with 0-10% DCM/MeOH) to give compound 136(50mg, 0.05mmol, 14% yield) after concentration of the pure fractions. Analytical method 3, t_R＝1.14min.[M+H]⁺＝974.4。

The compounds in table 31 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 136 in example 8.43.

Table 31:

example 8.44: (3R,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 167).

Step 1: allyl ((S) -1- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) (methyl) amino) -3-methoxy-1-oxoprop-2-yl) carbamate (27-1)

To a solution of F-4(2.049g, 3.91mmol) in anhydrous 1, 4-dioxane (7mL) was added HCl in 1, 4-dioxane (5.87mL, 23.46mmol) at 0 ℃. The cooling bath was removed and the resulting mixture was stirred at room temperature overnight. Once LCMS showed complete consumption of the starting material, the reaction mixture was concentrated to give 27-1 as a white solid, which was used for the next step without purification. Analytical method 5, t_R＝1.02min,[M+H]⁺＝424.3。

Step 2: 2- ((R) -2- ((R) -3- ((S) -2- (((allyloxy) carbonyl) amino) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4- (tert-butoxy) -4-oxobutyl) -6-methylpyridine 1-oxide (27-2)

At 0 deg.C, in27-1(1.8g, 3.91mmol) and A34(1.212g, 4.11mmol) in ACN (10mL) were added DIPEA (2.049mL, 11.73mmol) and HATU (1.561g, 4.11 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 1.5 hours. Once LCMS showed complete consumption of the starting material, the reaction mixture was diluted with 100mL EtOAc and 3 × 100mL with 5% NaHCO₃And brine, dried over sodium sulfate, filtered, and concentrated to give 27-2 as a brown foamy solid, which was used in the next step without purification. Analytical method 5, t _R＝1.10min,[M+H]⁺＝701.6。

And step 3: 2- ((R) -2- ((R) -3- ((S) -2-amino-3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4- (tert-butoxy) -4-oxobutyl) -6-methylpyridine 1-oxide (27-3)

To a solution of 27-2(2.74g, 3.91mmol) in DCM (30mL) were added N, N,1,1, 1-pentamethylsilylamine (3.13mL, 19.55mmol) and Pd (PPh)₃)₄(0.339g, 0.293mmol) and the resulting mixture stirred at room temperature for 2 hours. Once LCMS showed complete consumption of starting material, the reaction mixture was then concentrated. The resulting brown oil was diluted with 100mL EtOAc and 3 × 100mL of 5% NaHCO₃And brine, dried over sodium sulfate, filtered and concentrated under reduced pressure overnight to give 27-3 as a yellow foamy solid (about 100% yield), which was used in the next step without purification. Analytical method 5, t_R＝0.97min,[M+H]⁺＝617.3。

And 4, step 4: 2- ((R) -4- (tert-butoxy) -2- ((R) -3- ((S) -2- ((S) -2- ((tert-butoxycarbonyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -4-oxobutyl) -6-methylpyridine 1-oxide (27-4)

To a solution of 27-3(2.413g, 3.91mmol) in anhydrous Acetonitrile (ACN) (20mL) at 0 deg.C was added Boc-L-alanine (0.777g, 4.11mmol), TEA (1.090mL, 7.82mmol) and HATU (1.561g, 4.11 mmol). The cooling bath was removed and the resulting mixture was stirred at room temperature for 3.5 hours. Once LCMS showed complete consumption of the starting material, the reaction mixture was diluted with 100mL EtOAc and 3 × 100mL with 5% NaHCO ₃And brine, dried over sodium sulfate, filteredAnd concentrated under reduced pressure overnight to give 27-4 as the desired product as a yellow foamy solid, which was used in the next step without purification. Analytical method 5, t_R＝1.11min,[M+H]⁺＝788.3。

And 5: 2- ((R) -3- ((R) -3- ((S) -2- ((S) -2-aminopropionamide) -3-methoxy-N-methylpropionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -2- (carboxymethyl) -3-oxapropyl) -6-methylpyridine 1-oxide (27-5)

To a solution of 27-4(3.08g, 3.91mmol) in dry DCM (12mL) at 0 deg.C was added TFA (12.05mL, 156 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour, then warmed to room temperature and stirred for 3 hours. Once LCMS showed complete consumption of starting material, the reaction mixture was concentrated under reduced pressure and chromatographed on 415g C18 column (using 0-50% ACN in water (using 0.1% NH) by ISCO column chromatography₄OH buffer) elution; product coming out at 40% ACN) and lyophilized to give 27-5(1.01g, 1.598mmol, 40.9% yield). Analytical method 5, t_R＝0.51min,[M+H]⁺＝632.3。

Step 6: 2- ((R) -3- ((S) -2- ((2- (4- (2- (((tert-butoxycarbonyl) (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -2- (carboxymethyl) -3-oxapropyl) -6-methylpyridine 1-oxide (27-6)

To a solution of 27-5(267mg, 0.422mmol) in DCM (10mL) was added E17(200mg, 0.422mmol) and acetic acid (0.072mL, 1.266 mmol). The resulting mixture was stirred at room temperature for 1 hour, then NaBH (OAc) was added₃(358mg, 1.688 mmol). The reaction mixture was stirred at room temperature for a further 2 hours. Once LCMS showed complete consumption of the starting material, the reaction mixture was diluted with 100mL EtOAc and 50mL of 5% NaHCO₃Washing with Na₂SO₄Dried, filtered and concentrated. The crude oily product was chromatographed on a C18 column (using 0-100% ACN in water (with 0.1% NH) by ISCO column chromatography₄OH) as buffer elution) and lyophilized to give 27-6(224mg, 0.205mmol, 48.7% yield). Analytical method 2, t_R＝1.97min,[M+H]⁺＝1089.1。

And 7: 2- (((3R,7S,10S,13R) -6- (2- (4- (2- (((tert-butoxycarbonyl) (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) -6-methylpyridine 1-oxide (27-7)

To a solution of 27-6(224mg, 0.205mmol) in anhydrous DCM (100mL) were added 2, 6-lutidine (0.718mL, 6.16mmol), HOAt (28.0mg, 0.205mmol) and HATU (313mg, 0.822mmol) and the resulting mixture was refluxed overnight in a 45 ℃ heating bath. Once LCMS showed complete consumption of the starting material, the reaction mixture was concentrated and the resulting residue was taken up in EtOAc (100mL) and 5% NaHCO ₃The aqueous solution (100mL) was partitioned. The separated organic phase was washed with 5% NaHCO₃(2X50mL) and brine (50mL) over Na₂SO₄Dried, filtered and concentrated. The crude oil (27-7) was used in the next step without purification. Analytical method 5, t_R＝1.19min,[M+H]⁺＝1071.1。

And 8: 2- (((3R,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) -6-methylpyridine 1-oxide (27-8)

To a solution of 27-7(220mg, 0.205mmol) in anhydrous DCM (10mL) was added TFA (2.371mL, 30.8mmol) at 0 ℃ and then the cooling bath was removed. The resulting mixture was stirred at room temperature for 3 hours. Once LCMS showed complete consumption of the starting material, the reaction mixture was poured into 100mL saturated NaHCO₃Neutralized and extracted with 100mL DCM. The separated organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 27-8 as an oil, which was used in the next step without purification. Analytical method 5, t_R＝1.06min,[M+H]⁺＝971.2。

And step 9: (3R,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 167)

To a solution of 27-8(199mg, 0.205mmol) in THF (20mL) was added saturated NH₄Cl (6.7mL), zinc powder (803mg, 12.28mmol) and citric acid (708mg, 3.69mmol), and the resulting mixture was stirred at room temperature for 20 min. Once LCMS showed complete consumption of starting material, the clear two-phase reaction solution was decanted and the top organic phase was separated (2 × 20mL THF was added to extract any remaining product). The combined organics were concentrated and the residue was taken up in 100mL DCM/100mL 5% NaHCO₃Diluted and dispensed in a separatory funnel overnight. The separated aqueous phase was extracted with 50mL of DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The resulting oil was purified by ISCO column chromatography on a 150g C18 column eluting with 0-50% ACN in water (with 0.1% TFA) to give the TFA salt of the desired product as a white powder after lyophilization. The product was repurified by preparative HPLC and lyophilized to give compound 167(21mg, 0.021mmol, 10.19% yield). Analytical method 2, t_ry＝2.76min,[M+H]⁺＝955.0。

The compounds in table 32 were synthesized from each intermediate shown in tables 1-7 and described in example 8 above, according to the procedure described for compound 167 in example 8.44.

Table 32:

example 8.45: (3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 170).

The title compound 170 was prepared according to the procedure described for compound 32 in example 8.28, step 9, starting from 28-1. Intermediate 28-1 was prepared according to the procedure described for compound 82 in example 8.22.

(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (3, 3-difluorocyclobutyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 165)

Step 1: allyl ((S) -1- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) (methyl) amino) -3-methoxy-1-oxoprop-2-yl) carbamate (22-1)

To a solution of intermediate F-4(6.92g, 13.21mmol) in dry 1, 4-dioxane (volume: 40mL) was added 4M HCl in 1, 4-dioxane (19.82mL, 79mmol) at 0 ℃. The cooling bath was removed and the resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure overnight to give 22-1 as a white solid (5.84g, 12.68mmol, 96% yield), which was used in the next step without purification. Analytical method 5, t_R＝0.99min,[M+H]⁺＝424.1。

Step 2: tert-butyl (S) -4- ((R) -3- ((S) -2- (((allyloxy) carbonyl) amino) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- (3, 3-difluorocyclobutyl) -4-oxobutyrate (22-2)

To a solution of A29(3.64g, 13.79mmol) in ACN (vol: 50mL) at 0 deg.C were added DIPEA (8.76mL, 50.1mmol) and HATU (5.24g, 13.79 mmol). The cooling bath was removed and the resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0 ℃ again and 22-1(5.77g, 12.53mmol) was added. The resultant was stirred at room temperature for 3 hours and additional a29(320mg, 0.1 eq) and HATU (470mg, 0.1 eq) were added and stirring continued for an additional 2 hours. The resulting mixture was concentrated and the resulting residue was taken up in 200mL of EtOAc. The organic phase is treated with 3X150mL5％NaHCO₃The solution was washed with 150mL brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluting with 0-100% EtOAc in heptane) to give 22-2 as a white foamy solid after concentration of the pure fractions under reduced pressure (5.2g, 7.76mmol, 61.9% yield). Analytical method 5, t_R＝1.29min,[M+H]⁺614.2 (as carboxylic acid).

And step 3: tert-butyl (S) -4- ((R) -3- ((S) -2-amino-3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- (3, 3-difluorocyclobutyl) -4-oxobutyrate (22-3)

To a solution of 22-2(1.7g, 2.54mmol) in anhydrous DCM (vol: 20mL) were added N, N,1,1, 1-pentamethylsilane amine (2.032mL, 12.68mmol) and Pd (PPh) ₃)₄(0.220g, 0.190mmol), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated and the residue was taken up in 100mL of EtOAc. The organic phase was washed with 3 × 100mL of 5% NaHCO₃And brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 22-3 as a yellow foam (1.487g, 2.54mmol, ca. 100% yield). The product was used directly in the next step without further purification. Analytical method 5, t_R＝1.15min,[M+H]⁺＝586.2。

And 4, step 4: (S) -4- ((R) -3- ((S) -2-amino-3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- (3, 3-difluorocyclobutyl) -4-oxobutyric acid (22-4)

To a solution of 22-3(2.087g, 3.56mmol) in dry DCM (14mL) at 0 deg.C was added TFA (13.72mL, 178 mmol). The cooling bath was removed and the resulting solution was stirred at room temperature for 30 minutes. Toluene (50mL) was then added and the reaction mixture was concentrated. The resulting brown residue was purified by reverse phase flash column chromatography (using 0-50% ACN in water (with 0.1% NH)₄OH) elution) and freeze-drying of the pure fraction gave 22-4(1.543g, 2.88mmol, 81% yield). Analytical method 2, t_R＝1.21min,[M+H]⁺＝530.0。

And 5: (S) -4- ((R) -3- ((S) -2- ((S) -2- ((2- (4- (2- (((tert-butoxycarbonyl) (tert-butyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) amino) propanamide) -3-methoxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3- (3, 3-difluorocyclobutyl) -4-oxobutanoic acid (22-5)

To a solution of DE3(881mg, 1.496mmol) in DMF (30mL) were added DIPEA (0.442mL, 2.53mmol) and HATU (569mg, 1.496mmol) and the resulting yellow solution was stirred at room temperature for 15 min. 22-4(610mg, 1.151mmol) was then added as a solid and stirring continued at room temperature for 15 minutes. The reaction mixture was then taken up in EtOAc and washed with brine (x 2). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude material was purified by reverse flash column chromatography (with 0-80% water/ACN (with 0.1% NH)₄OH) elution) and freeze drying the pure fractions to yield 22-5(2.5g, 2.27mmol, 95%) as an off-white powder. Analytical method 5, t_R＝0.93min,[M+H]⁺＝1100.8。

Step 6: (3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (3, 3-difluorocyclobutyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 165)

Step 6-1: to a 1L round bottom flask containing 22-5(1.3g, 1.181mmol) in DCM (650mL) was added HATU (1.796g, 4.72mmol), HOAt (0.161g, 1.181mmol) and 2, 6-lutidine (4.13mL, 35.4mmol) with stirring at room temperature. The resulting mixture was stirred at room temperature for 15 minutes and then heated to 42 ℃. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated to a volume of about 1/3 and taken with half-saturated NaHCO ₃And (4) washing the solution. The organic phase was then dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography (eluting with 0-10% DCM/MeOH) to afford the cyclized product after drying of the pure fractions (2.16g, 1.99mmol, 86%). Analytical method 5, t_R＝1.43min,[M+H]⁺＝1084.8。

Step 6-2: deprotection step-to a round bottom flask containing the cyclized product from step 6-1 (2.16g, 1.994mmol) was added DCM (40 mL). The resulting clear solution was cooled in an ice bath and TFA (7.68ml, 10) was slowly added dropwise0 mmol). Once complete consumption of the starting material was observed, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour, then added dropwise to saturated NaHCO₃(105ml, 120mmol) in a pre-cooled solution in an ice bath. The reaction mixture was stirred at room temperature for 1 hour or until evolution of gas ceased, then poured into a separatory funnel and shaken until no sound of gas evolved. The organic phase was separated and the aqueous portion was back-extracted with DCM (× 1). The combined organic phases were dried over sodium sulfate, filtered and concentrated to give a viscous oil. The crude product was purified by flash column chromatography (eluting with 0-20% DCM/MeOH), concentrated and lyophilized to give compound 165 as a white solid (1.55g, 1.56mmol, 78%, main product; analytical method 3, t;, analytical method 3) _R＝1.13min.，[M+H]⁺982.4) and compound 166 as a white solid (127mg, 0.14mmol, 6.8%, minor product, see table 33).

Table 33:

example 8.46: (3R,7S,10S,13R) -7- (2-aminoethyl) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (Compound 178)

Step 1: (R) -methyl 4- ((R) -3- ((S) -2-amino-3- ((tert-butyldimethylsilyl) oxy) propionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -3-benzyl-4-oxobutyrate (30-1)

To Fmoc-Ser (OtBME)₂To a solution of Si) OH (548mg, 1.242mmol) in DMA (5mL) was added HATU (455mg, 1.197mmol) and DIPEA (0.789mL, 4.52 mmol). The resulting mixture was stirred at room temperature for 2 minutes and then added to a solution of intermediate M-2(484mg, 1.129mmol in 3mL DMA). The reaction mixture was stirred at room temperature for 3 hours. Addition of additional Fmoc-Ser (OtBME)₂Si) OH (88mg, 0.200mmol) and HATU (76mg, 0.20mmol) and stirring was continued at room temperature overnight. 4-methylpiperidine (0.8mL, 6.77mmol) was added and stirring was continued at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure (bath temperature 50 ℃) and the residue was purified by reverse flash column chromatography (with 5% -90% water/ACN (with 0.1% NH) ₄OH) elution) and freeze-dried the pure fractions to yield 30-1(450mg, 0.664mmol, 59%). Analytical method 5, t_R＝1.41min,[M+H]⁺＝630.5。

Step 2: (R) -methyl 3-benzyl-4- ((R) -3- ((S) -2- ((S) -4- ((tert-butoxycarbonyl) amino) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) butanamide) -3- ((tert-butyldimethylsilyl) oxy) propionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutyrate (30-2)

To a solution of DE4(449mg, 0.785mmol) and 30-1(450mg, 0.714mmol) in DMA (5mL) was added DIPEA (0.374mL, 2.142 mmol). The resulting solution was stirred at room temperature for 2 minutes, then a solution of HATU (299mg, 0.785mmol) in DMA (3mL) was added. The reaction mixture was stirred at room temperature for 3 hours. Additional DE4(88mg, 0.14mmol) and HATU (76mg, 0.20mmol) were added and stirring continued at room temperature overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography eluting with 98/2 to 85/15DCM/MeOH with 0.3% triethylamine to give 30-2 as the major product after concentration of the pure fractions (760mg, 0.642mmol, 90% yield). Analytical method 5, t_R＝1.55min,[M+H]⁺＝1184.1。

And step 3: (R) -3-benzyl-4- ((R) -3- ((S) -2- ((S) -4- ((tert-butoxycarbonyl) amino) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) butanamide) -3- ((tert-butyldimethylsilyl) oxy) propionamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutanoic acid and

Mixture of (R) -3-benzyl-4- ((R) -3- ((S) -2- ((S) -4- ((tert-butoxycarbonyl) amino) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) butanamide) -3-hydroxypropanamide) -3- (4-chlorobenzyl) piperidin-1-yl) -4-oxobutanoic acid (30-3)

To a solution of 30-2(770mg, 0.65mmol) in DMA (5mL) was added water (1mL) and THF (4 mL). The resulting mixture was stirred at room temperature, then LiOH solution (1.300mL, 1.300mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Additional LiOH (1.300mL, 1.300mmol) was added and stirring continued at room temperature overnight (LCMS indicated a mixture of the desired product and desiliconized alkyl alcohol R ═ H). The reaction mixture was cooled in an ice bath, the pH was neutralized (pH 7) by addition of 1N HCl, then concentrated under reduced pressure (bath maintained at 30 ℃). The residue was taken up in 250mL EtOAc. The organic phase was washed with water and brine, over Na₂SO₄Dried, filtered and concentrated to give 30-3(770mg, white solid) as a mixture of two products (R ═ H and TBS in a ratio of 1: 1.2). The mixture was used in the next step without further purification. TBS, analytical method 2, t_R＝2.41min,[M+H]⁺1171.7.R ═ H, analytical method 2, t _R＝1.98min,[M+H]⁺＝1055.1。

And 4, step 4: tert-butyl (2- ((3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -2,5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-7-yl) ethyl) carbamate (30-4) and tert-butyl (2- ((3R,7S,10S,13R) -3-benzyl-10- (((tert-butyldimethylsilyl) oxy) methyl) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -2,5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-7-yl) ethyl) carbamate (30-5)

To a 1L round bottom flask containing a solution of mixture 30-3(770mg, 0.658mmol) in DCM (700mL) was added 2, 6-lutidine (2.3mL, 19.74mmol), HOAt (107mg, 0.790mmol), and HATU (1001mg, 2.63 mmol). The resulting mixture was heated to 50 ℃ for 4 hours in a heating bath and then stirred at 38 ℃ overnight. The reaction mixture was then concentrated to dryness under reduced pressure, and the residue was taken up in EtOAc (400mL) and 5% NaHCO₃The aqueous solution (30mL) was partitioned. Will be provided withThe organic phase was washed with 5% NaHCO₃Aqueous (2 × 25mL) and brine (30mL) and washed over Na ₂SO₄Dried, filtered and concentrated. The crude material was purified by reverse flash column chromatography eluting with 5% -60% water/ACN (with 0.1% trifluoroacetic acid) to give 30-4 as a white solid after freeze drying of the corresponding pure fractions (300mg, 0.21mmol, 32% yield, analytical method 2, t._R＝3.22min，[M+H]⁺1039.4) and 30-5 as a white solid (360mg, 0.30mmol, 45% yield, analytical method 5, t_R＝1.55min，[M+H]⁺＝1153.7)。

And 5: (1S,3R,7S,10S,13R) -7- (2-aminoethyl) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (compound 178)

To a round bottom flask containing 30-5(350mg, 0.304mmol) in anhydrous dioxane (6mL) and cooled in an ice bath was added 4.0N hydrogen chloride in dioxane (2mL, 8.00 mmol). The ice bath was then removed and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give an off-white solid which was purified by reverse flash column chromatography eluting with 5% -50% water/ACN (with 0.1% trifluoroacetic acid) to give compound 178(200mg, 0.181mmol, 59.5%), analytical method 3, t _R＝0.94min.，[M+H]⁺＝937.39。

Example 8.47: (3S,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone trifluoroacetate (compound 177)

Step 1: tert-butyl (R) -3- ((S) -3- ((((((9H-fluoren-9-yl) methoxy) carbonyl) -L-alanyl) oxy) -2- ((S) -2- ((((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propionamide) -N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (31-1)

To a solution of intermediate G (291mg, 0.588mmol) and Fmoc-Ala-OH (187mg, 0.600mmol) in acetonitrile (30mL) at room temperature was added DIPEA (0.205mL, 1.176mmol) followed by HATU (228mg, 0.600 mmol). The resulting mixture was stirred at room temperature for 1 hour. Once the desired product was observed to be the major product, acetonitrile was removed under reduced pressure. The crude residue was dissolved in 300mL EtOAc and taken up with 40mL saturated NaHCO₃And (4) washing with an aqueous solution. The separated organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue obtained was dissolved in DCM and purified by ISCO column chromatography on a 40g silica gel column (eluting with 10% -100% EtOAc in heptane) to give 31-1 as a foamy solid (210mg, 0.207 mmol). Analytical method 5, t _R＝1.51min,[M+H(-Boc)]⁺＝971.2。

Step 2: (S) -2- ((S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propionamide) -3- (((R) -3- (4-chlorobenzyl) piperidin-3-yl) (methyl) amino) -3-oxapropyl (((9H-fluoren-9-yl) methoxy) carbonyl) -L-alanine ester (31-2)

To a solution of 31-1(210mg, 0.207mmol) in anhydrous ethyl acetate (7mL) at 0 ℃ 4M hydrogen chloride in dioxane (1mL, 4.00mmol) was added portionwise. The resulting mixture was stirred at 0 ℃ for 1 hour and then at room temperature overnight. Once the desired product was observed by LCMS, the reaction mixture was concentrated and the resulting solid was dried under reduced pressure and then lyophilized to give 31-2(192.5mg, 0.172mmol, 83% yield). Analytical method 5, t_R＝1.45min,[M+H]⁺＝912.6。

And step 3: tert-butyl (S) -3- ((R) -3- ((S) -3- ((((((9H-fluoren-9-yl) methoxy) carbonyl) -L-alanyl) oxy) -2- ((S) -2- ((((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propionamide) -N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoate (31-3)

To a solution of 31-2(192.5mg, 0.179mmol) and C1(45.9mg, 0.179mmol) in acetonitrile (20mL) was added DIPEA (0.094mL, 0.538mmol) followed by HATU (68.2mg, 0.179mmol) and the resulting mixture was stirred at room temperature for 3 And (4) hours. Once the desired product was observed by LCMS, the acetonitrile was removed under reduced pressure and the crude residue was dissolved in 200mL of EtOAc. The organic phase was washed with 30mL of 5% NaHCO₃30mL of saturated NH₄And (5) washing with an OH solution. The separated organic phase was washed with brine (2 × 30mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 31-3(220mg, 0.172mmol, 96% yield), which was used in the next step without purification. Analytical method 5, t_R＝1.54min,[M+H]⁺Analytical method 5, t 971.2_R＝1.54min,[M+H]⁺Not observed due to lack of ionization.

And 4, step 4: (S) -3- ((R) -3- ((S) -3- (((((9H-fluoren-9-yl) methoxy) carbonyl) -L-alanyl) oxy) -2- ((S) -2- ((((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propionamide) -N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (31-4)

To a solution of 31-3(220mg, 0.172mmol) in dry DCM (4ml) was added TFA (1.06ml, 13.76mmol) portionwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour 30 minutes, then cooled to 0 ℃ and diluted with 20mL of DCM and 5mL of water. Slowly add Na₂CO₃(1.893ml, 3.79mmol) to adjust the pH to 6.5-7. The resulting mixture was extracted with 15/85 isopropanol/DCM (120 mL). Adding Na to the organic matter ₂SO₄Dried and concentrated to dryness to give 31-4(220mg, 86% purity), which was used in the next step without purification. Analytical method 5, t_R＝1.00min,[M+H]⁺＝1094.8。

And 5: (S) -3- ((R) -3- ((S) -2- ((S) -2-aminopropionamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (31-5)

To a solution of 31-4(220mg, 86% purity) in DCM (9mL) was added 4-methylpiperidine (1mL, 7.86mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated and diluted with 50/50 acetonitrile/water (10 mL). Passing the resulting mixture through

The pad was filtered and washed with acetonitrile/water. Concentrating the filtrate to obtainThe residue obtained is taken up with 2mL of ACN and 1M NaHCO₃(1.0mL, 1.000mmol) were mixed. The crude product was chromatographed on an ISCO column using a C18 column (100g) (with ACN/water (with 0.1% NH)₄OH) elution) and freeze dried to afford 31-5 as a white solid (77mg, 0.133mmol, 73% yield). Analytical method 7, t_R＝0.73min,[M+H]⁺＝579.2。

Step 6: (S) -3- ((R) -3- ((S) -2- ((S) -2- ((2- (4- (2- (((tert-butoxycarbonyl) (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) amino) propionamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (31-6)

To a solution of 31-5(77mg, 0.133mmol) in DCM (12mL) was added E17(66.2mg, 0.140mmol), and the resulting solution was stirred at room temperature for 1 hour. Addition of NaBH (OAc)₃(85mg, 0.399mmol) followed by the addition of acetic acid (0.023mL, 0.399mmol) and stirring continued at room temperature for an additional 1 hour. Once LCMS showed complete consumption of the starting material, acetic acid (0.023mL, 0.399mmol) and 0.1mL water were added to quench the reaction. The mixture was diluted with 100mL of DCM/IPA mixture (80/20) and 20mL of 5% NaHCO₃And 20mL brine, over Na₂SO₄Dried, filtered and concentrated. The crude product was chromatographed on an ISCO column using 100g C18 column (with 5% -70% ACN in water, 0.1% NH)₄OH elution) and lyophilized to give 31-6(86mg, 0.079mmol, 59.2% yield). Analytical method 5, t_R＝0.88min,[M+H]⁺＝1036.7。

And 7: (S) -3- ((R) -3- ((S) -2- ((S) -2- ((2- (4- (2- (((tert-butoxycarbonyl) (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) amino) propanamide) -3- ((tert-butyldimethylsilyl) oxy) -N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carbonyl) -5,5, 5-trifluoropentanoic acid (31-7)

Tert-butyldimethylsilyl chloride (50.0mg, 0.332mmol) was added dropwise to a solution of 31-6(86mg, 0.083mmol) and imidazole (16.94mg, 0.249mmol) in DCM (20mL) at 0 deg.C. The resulting mixture was stirred at room temperature for 16 hours. Additional imidazole (200mg, 2.93mmol) and tert-butyldimethylsilyl were added Alkyl chloride (440mg, 2.90mmol) and stirring at room temperature was continued for 5 h. Imidazole (100mg, 1.46mmol) and tert-butyldimethylsilyl chloride (220mg, 1.46mmol) were again added and stirring continued at room temperature for a further 18 h. Once LCMS showed complete consumption of starting material, the reaction mixture was transferred to a 500mL separatory funnel and 200mL DCM was added. The organic phase was washed with water (40mL) and brine (40mL) and washed with Na₂SO₄Dried, filtered and concentrated. The crude residue was loaded on a C18 column (with 5% -70% ACN/water (5% -70%) (with NH)₄OH) elution). The product-containing fractions were lyophilized to give 31-7(50mg, 0.040mmol, 48.2% yield). Analytical method 2, t_R＝2.53min,[M+H]⁺＝1051.2。

Step 8 tert-butyl ((5- (4- (2- (((3S,7S,10S,13R) -10- (((tert-butyldimethylsilyl) oxy) methyl) -13- (4-chlorobenzyl) -7, 12-dimethyl-2, 5,8, 11-tetraoxo-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecan-6-yl) methyl) -5-chloro-3-fluorophenoxy) phenyl) -1-methyl-1H-imidazol-2-yl) methyl) (methyl) carbamate (31-8)

To a solution of 31-7(62mg, 0.054mmol) in anhydrous DCM (40mL) was added 2, 6-lutidine (0.094mL, 0.808mmol) and HOAt (7.33mg, 0.054 mmol). The resulting mixture was stirred at room temperature for 2 min, then HATU (106mg, 0.215mmol) was added. The reaction mixture was then heated in a heating bath at 46 ℃ for 7 hours. The crude mixture was filtered and the filtrate was concentrated. The residue obtained was dissolved in 60mL of EtOAc. The organic phase was washed with 10mL of 5% NaHCO ₃The solution was washed with 10mL brine, Na₂SO₄Dried, filtered and concentrated. The crude product was purified by ISCO column chromatography on silica gel (eluting with DCM: 15% MeOH/DCM 0.3% TEA) to give 31-8(56mg, 0.045mmol, 84% yield). Analytical method 5, t_R＝1.60min,[M+H]⁺＝1143.7。

Step 9.(3S,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone (compound 177)

To a solution of 31-8(56mg, 0.045mmol) in EtOAc (3.5mL) at 0 ℃ was added 4M hydrogen chloride in dioxane (0.5mL, 2.000 mmol). The cooling bath was removed and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was stored at 4 ℃ and then concentrated at room temperature. The residue was dissolved in ACN/water (60/40) and purified by reverse phase column chromatography on a C18 column eluting with ACN/water (with 0.1% TFA). The product fractions were lyophilized to give compound 177(8.2mg, 7.15 μmol, 15.72% yield). Analytical method 2, t_R＝2.68min,[M+H]⁺＝919.2。

Example 8.47: synthesis of tert-butyl (R) -3- ((S) -2- ((S) -2-aminopropionamide) -3- (difluoromethoxy) -N-methylpropionamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (intermediate L)

Step 1. tert-butyl (R) -3- ((S) -2- ((S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propanamide) -3-hydroxy-N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (L-1)

To a vial containing intermediate G (250mg, 0.59mmol) and Fmoc-Ala-OH (183mg, 0.59mmol) was added DMF (4 mL). DIPEA (0.154mL, 0.880mmol) was added followed by HATU (223mg, 0.59 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was taken up in EtOAc and washed with half-saturated sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash column (0-100% EtOAc/heptane elution) to afford L-1 as a foam after drying of the pure fractions (364mg, 0.51mmol, 86%).

Step 2. tert-butyl (R) -3- ((S) -2- ((S) -2- ((((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propanamide) -3- (difluoromethoxy) -N-methylpropanamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (L-2)

To a 20mL vial containing a mixture of L-1(364mg, 0.506mmol), sodium sulfate (71.9mg, 0.506mmol), and copper (I) iodide (96mg, 0.506mmol) was added ACN (2 mL). The resulting mixture was stirred at 60 ℃ and then slowly treated over 45 minutes (using a syringe pump) with a solution of 2, 2-difluoro-2- (fluorosulfonyl) acetic acid (0.078mL, 0.759mmol) in anhydrous acetonitrile (ACN, 2 mL). The reaction mixture was then stirred for 30 minutes, filtered, and washed with DCM. The filtrate was then washed with water (x1), dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (eluting with 0-30% DCM/EtOAc) to give L-2 as a white foam (169mg, 0.220mmol, 43.4% yield) after drying the pure fractions.

Step 3. tert-butyl (R) -3- ((S) -2- ((S) -2-aminopropionamide) -3- (difluoromethoxy) -N-methylpropionamide) -3- (4-chlorobenzyl) piperidine-1-carboxylate (intermediate L)

To a vial containing L-2(169mg, 0.220mmol) in ACN (2mL) was added 4-methylpiperidine (0.778mL, 6.59mmol) cooled in an ice bath. After addition, the ice bath was removed, and the resulting mixture was stirred at room temperature for 2 hours, then concentrated. The resulting crude product was purified by flash column chromatography on silica gel (eluting with 0-20% DCM/MeOH), and after drying the pure fractions, INT L was obtained as a foam (99mg, 0.18mmol, 82%).

Example 9: post-modification-in this section, modifications performed after cyclization of the linear peptide are described.

Example 9.1: synthesis of (2S,5S,8R,12R) -12-benzyl-1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -2,7, 10-trimethyl-5- (2-oxapropyl) -1,4,7, 10-tetraaza-cyclotetradecane-3, 6,11, 14-tetraone hydrochloride (Compound 129)

Step 1: to compound 135(32mg, 0.027mmol) dissolved in DCM (2mL) were added DMAP (5.0mg, 0.041mmol), 2-dimethyl-1, 3-dioxane-4, 6-dione (5.1mg, 0.035mmol) and DIC (5.5 μ L, 0.035mmol), and the resulting mixture was stirred at room temperature for 45 hours. Additional DMAP (0.7mg, 5.4 μmol), 2-dimethyl-1, 3-dioxane-4, 6-dione (0.8mg, 5.4 μmol) and DIC (0.9 μ L, 5.4 μmol) were added and stirring continued at room temperature for 20 hours.

Step 2: aqueous 80% TFA (2mL) was added to the mixture of step 1. The reaction mixture was stirred at room temperature for 5 hours, then concentrated to dryness in vacuo. The residue was dissolved in DCM (2mL) and 80% aqueous TFA (2mL) and the resulting mixture was stirred at rt for 16 h and at 50 ℃ for 2 h, then concentrated to dryness in vacuo.

Step 3. dissolving the residue from step 2 in ACN/H₂O (1:1) (4 mL). The resulting solution was stirred at room temperature for 16 hours and at 50 ℃ for 2 hours, then concentrated to dryness in vacuo. The crude product is passed through preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) is purified. Pure fractions were combined and lyophilized. The product was dissolved in EtOAc (40mL) and the organic phase was washed with 5% NaHCO₃Aqueous (2X5mL) and brine (5mL) and washed with Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. Dissolving the residue in ACN/H₂O (1:1) (20mL) and 0.023M aqueous HCl (5.1mL) was added. After lyophilization, the hydrochloride salt of compound 129 was obtained as a white solid (18.4mg, 0.017mmol, 64% yield). Analytical method 9; t is t_R＝5.15min；[M+H]⁺＝948.4。

Example 9.2: synthesis of (2S,5S,8R,12S) -2- (3- (azetidin-1-yl) -3-oxapropyl) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -3, 3-dimethyl-2, 3-dihydro-1H-inden-1-yl) -5- (methoxymethyl) -7, 10-dimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone hydrochloride (Compound 132).

132A (40.6mg, 0.032mmol) and TBTU (15.3mg, 0.048mmol) were dissolved in DMA (1.5mL) and DIEA (0.011mL, 0.064mmol) and the resulting mixture was stirred at room temperature for 2 min. A suspension of azetidine HCl (4.5mg, 0.048mmol) in DMA (0.5mL) and DIEA (8.3. mu.l, 0.048mmol) was added and stirring continued at room temperature for 3And 0 minute. Additional TBTU (5.03mg, 0.016mmol) and DIEA (2.7. mu.l, 0.016mmol) were added, followed by a suspension of azetidine HCl (1.5mg, 0.016mmol) in DMA (0.1mL) and DIEA (2.7. mu.l, 0.016 mmol). The reaction mixture was stirred at room temperature for 105 minutes and at 50 ℃ for 30 minutes. Azetidine HCl (4.4mg, 0.047mmol) in DMA (0.5mL) and DBU (7.1. mu.l, 0.047mmol) was added again at room temperature and stirring was continued for 45 minutes at room temperature. The reaction mixture was purified by addition of MeOH (1mL) and H₂O quench and the product is passed through preparative reverse phase HPLC (eluent A: H)₂0.1% TFA in O; eluent B: ACN) was isolated. Pure fractions were combined and lyophilized. The product was dissolved in EtOAc (50mL) and the organic phase was washed with 5% NaHCO₃Aqueous solution (2 × 5mL) and brine, washed over Na₂SO₄Dried, filtered, and concentrated to dryness in vacuo. Dissolving the residue in ACN/H ₂O (1:1) (20mL) and 0.016M aqueous HCl (5.1mL) was added. After lyophilization, the hydrochloride salt of compound 132 was obtained as a white solid (14mg, 0.011mmol, 34% yield). Analytical method 9; t is t_R＝5.29min；[M+H]⁺＝1087.5。

Example 9.2: synthesis of (3S,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2, 5-dihydro-1H-pyrrol-3-yl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone hydrochloride (Compound 77)

To a solution of DMA (2mL) in 77A was added 37% formaldehyde solution (0.019mL, 0.261mmol), and the resulting solution was stirred at room temperature for 30 minutes. Then NaBH (OAc) is added₃And stirring was continued at room temperature for 2 hours and 30 minutes. An additional 37% formaldehyde solution (6.5 μ l, 0.087mmol) was added and the resulting mixture was stirred at room temperature for 10 min. Add NaBH (OAc) again₃And stirring was continued at room temperature for 80 minutes. Subjecting the reaction mixture to hydrogenation with H₂O (2mL) quench and pass the product throughPreparative reverse phase HPLC (eluent A: H)₂0.01M HCl in O; eluent B: ACN) was isolated. Pure fractions were combined and lyophilized to give compound 77 as a white solid (30mg, 0.030mmol, 34% yield). An analytical method 14; t is t _R＝4.48min；[M+H]⁺＝958.4。

Example 10: PCSK9 ligand binding assay.

PCSK9 binding of compounds of the present disclosure was measured using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The time-resolved fluorescence resonance energy transfer (TR-FRET) assay measures the ability of a compound of the disclosure to interfere with the binding of human PCSK9 to human LDLR, providing potency (IC)₅₀) And efficacy (A)_max) Is measured.

Material

Human PCSK9

Human PCSK9 Alexa Fluor 647

Human LDLR extracellular domain europium Krypton

Proxi plate Low-volume measuring plate (PerkinElmer #6008280)

Greiner V type base (Greiner BioOne company #781280)

Assay buffer

ο20mM HEPES，pH 7.5

ο150mM NaCl

ο1mM CaCl₂

ο0.01％v/v Tween20

ο0.01％w/v BSA

Master compound plates were prepared in GreinerV type base plates by diluting the compounds of the present disclosure in dimethylsulfoxide to the correct concentration based on the desired maximum concentration of the desired final concentration: the master plate concentration was 1.5mM (68uL DMSO +12uL 10mM compound of the disclosure) for a final concentration of 30uM, 0.5mM (76uL DMSO +4uL 10mM compound of the disclosure) for a final concentration of 10uM, and 150uM (69uL DMSO +1uL 10mM compound of the disclosure) for a final concentration of 3 uM. These solutions were pipetted into columns 1 and 11 of the compound plate. Three-fold serial dilutions were generated in columns 2-10 and 12-20 of compound plates by transferring 10uL into 20uL DMSO. Columns 21 and 22 of the compound plate are negative controls containing DMSO alone.

An intermediate plate was created in a Greiner V-type bottom plate by transferring 8uL from each well of the master plate to the corresponding well containing 92uL of assay buffer and mixing well.

The assay was performed using a Proxi plate low capacity assay plate. To all wells of the plate 10uL of 16nM human PCSK9 Alexa Fluor 647 was added followed by 5uL from the intermediate plate. For positive control wells in columns 23 and 24 of the plate, 5uL of unlabeled human PCSK9 (to 4uM in assay buffer containing 8% DMSO) was added. After 30 min incubation, 5uL of 4nM human LDLR ectodomain-europium krypton were added and the mixture was incubated for an additional 2 hours.

The TR-FRET signal was measured on an EnVision or PheraStar instrument with a 60ms delay, 330nM excitation and 665nM emission (FRET), and 330nM excitation and 615nM (europium). The FRET ratio (FRET/europium) was used for the calculation.

Data analysis

In columns 21 and 22 of the compound plates, no inhibition (0%) was observed from wells containing DMSO (control). In columns 23 and 24 of the plate, complete inhibition (100%) was observed from wells containing 1uM of human PCSK9 (control). Data are expressed as percent inhibition: (value-0%)/(100% -0%).

Table 34: the cyclic polypeptides of the disclosure have PCSK9 activity in the PCSK9 Fret assay.

Equivalents of

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed by the scope of the following claims.

Claims

1. A compound having the formula (I):

wherein:

when X is present₁And X₂Each independently is H or (C)₁-C₆) Alkyl or X₁And X₂Together with the carbon atom to which they are attached form ═ (O) or X₃is-CH₂-, or when X₁And X₂Together with the carbon atom to which they are attached form ═ (O) or X₃is-O-, -NH-or-N (C)₁-C₆) Alkyl-;

R₂is H, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₁-C₆) HalogenAlkyl radicals, -NR₁₂R₁₃、(C₃-C₇) Carbocyclyl group, (C)₃-C₇) Cycloalkenyl, 5-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, (C)₆-C₁₀) Aryl, or a 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the alkyl is optionally substituted with one or more R ₁₈Substituted, and the carbocyclyl, (C)₃-C₇) Cycloalkenyl, heterocyclyl, aryl and heteroaryl optionally substituted with one or more R₁₉Substitution;

R₄is H or (C)₁-C₆) An alkyl group; or

R₈is H, (C)₁-C₆) Alkyl, or (C)₁-C₆) Haloalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of: (C)₃-C₇) Carbocyclyl, 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, -NR ₁₆R₁₇and-C (O) NR₁₆R₁₇；

R₁₂and R₁₃Each independently is H or (C)₁-C₆) An alkyl group;

R₁₅and R_15’Each independently is H or (C)₁-C₆) An alkyl group;

R₁₆and R₁₇Each independently is H or (C)₁-C₆) Alkyl, or

R₂₁is H or (C)₁-C₆) An alkyl group;

each R₂₂Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl radical、(C₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, CN, (C)₆-C₁₀) Aryl, or 5-or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein said aryl and heteroaryl are optionally substituted with one or more R ₂₃Substitution;

each R₂₃Independently at each occurrence, is halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -CH₂(OCH₂CH₂)_1-3OCH₂CH₃-OH, CN, or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, wherein the heterocyclyl is optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -C (O) R₂₄R₂₅、-NR₂₄C(O)R₂₅、-NH₂、-NH(C₁-C₆) Alkyl and-N ((C)₁-C₆) Alkyl radical)₂And said alkyl is optionally substituted by-NR₂₄R₂₅Substituted, or a 4-to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O and S, optionally substituted with one or more substituents each independently selected from: halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Haloalkoxy, -OH, -NH₂、-NH(C₁-C₆) Alkyl and-N ((C)₁-C₆) Alkyl radical)₂(ii) a And is

2. The compound of claim 1, wherein R₄Is H or (C)₁-C₆) An alkyl group.

3. The compound of claim 1 or 2, wherein R₄Is H.

4. The compound of claim 1, wherein R₃And R₄Together with the atoms to which they are attached form a 5-to 7-membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S.

5. The compound of claim 4, wherein R₃And R₄Together with the atoms to which they are attached form a 6 membered heterocyclyl ring comprising 1-3 heteroatoms selected from N, O and S.

6. The compound of any one of claims 1-5, wherein R₅Is H or (C)₁-C₆) An alkyl group.

7. The compound of any one of claims 1-6, wherein R₅Is (C)₁-C₆) An alkyl group.

8. The compound of any one of claims 1-7, wherein R₇Is H or (C)₁-C₆) An alkyl group.

9. The compound of any one of claims 1-8, wherein R₇Is (C)₁-C₆) An alkyl group.

10. The compound of any one of claims 1-9, wherein R₉Is a halogen.

11. The compound of any one of claims 1-10, wherein R₉Is chlorine.

12. The compound of any one of claims 1-11, wherein R₈Is optionally substituted with one to three substituents each independently selected from (C)₁-C₆) Alkyl groups: (C) ₃-C₇) Carbocyclyl, 4-to 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, -NR₁₆R₁₇and-C (O) NR₁₆R₁₇。

13. The compound of any one of claims 1-12, wherein R₈Is (C)₁-C₆) An alkyl group.

14. The compound of claim 1, having formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), or formula (Ii):

15. the compound of any one of claims 1-14, wherein R₁Is phenyl, which is-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution.

16. The compound of any one of claims 1-14, wherein R₁Is a pyridyl radical, which is-OR₁₀Substituted and optionally substituted with one to three R₁₁And (4) substitution.

17. The compound of claim 1, having formula (Ij), formula (Ik), formula (Im), or formula (Io):

wherein x is 0, 1 or 2.

18. The compound of any one of claims 1-17, wherein R₁₀Is substituted by one to three R₂₂A substituted phenyl group.

19. The compound of any one of claims 1-17, wherein R₁₀Is substituted by one to three R₂₂A substituted pyridyl group.

20. The compound according to claim 1, selected from:

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine 1-oxide;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((cyclobutylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (4- ((dimethylamino) methyl) -5-methyl-1H-imidazol-1-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- (cyclopropylmethyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((R) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-5-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- ((5-chloro-3- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) pyridin-2-yl) methyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (pyridin-3-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (pyridin-3-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -3-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3-ethyl-10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- (azetidin-1-ylmethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- ((5-chloro-3- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) pyridin-2-yl) methyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- ((difluoromethoxy) methyl) -7-methyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- ((5- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-2-yl) oxy) benzyl) -13- (4-chlorobenzyl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- ((5- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-2-yl) oxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- (azetidin-1-ylmethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (2, 6-difluorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (oxazol-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6- (2,2, 2-trifluoroethoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (2,4, 6-trifluorobenzyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2-fluoro-6- (4- (5-methyl-4- (pyrrolidin-1-ylmethyl) -1H-imidazol-1-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3- ((E) -but-2-en-1-yl) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- (cyclopropylmethyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) -3-fluorophenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- ((1-methyl-6-oxo-1, 6-dihydropyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((cyclobutylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,4, 6-trifluorobenzyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (morpholinomethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (pyridin-3-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,3, 4-trifluorobenzyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3-propyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -5-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -6- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (5- ((dimethylamino) methyl) -4-methyl-4H-1, 2, 4-triazol-3-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- (2, 2-difluoroethyl) -10- (hydroxymethyl) -7-methyl-1, 4,6,9, 12-pentazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- (((S) -3-hydroxypyrrolidin-1-yl) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 4,6,9, 12-pentazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((4-hydroxypiperidin-1-yl) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (4- (trifluoromethyl) benzyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3-ethyl-10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- ((S) -1-hydroxyethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) pyridine 1-oxide;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -3-isopropyl-7-methyl-1, 4,6,9, 12-pentazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (1-methylazetidin-3-yl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((R) -1- (dimethylamino) ethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- (((S) -3- (dimethylamino) pyrrolidin-1-yl) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -6- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-fluorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -6- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -5-fluorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-13- (4-chlorobenzyl) -6- (2, 4-difluoro-6- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (1-methyl-2- ((4-methylpiperazin-1-yl) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2, 5-dihydro-1H-pyrrol-3-yl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-4-oxa-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (3- (trifluoromethyl) benzyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -5- (hydroxymethyl) -2,7, 10-trimethyl-12- ((1R,3S) -3-methyl-2, 3-dihydro-1H-inden-1-yl) -1,4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- ((5-chloro-3- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) pyridin-2-yl) methyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -2, 3-dihydro-1H-inden-1-yl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) -2-fluorophenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-ethyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(2S,5S,8R,12R) -12-benzyl-1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -5- (hydroxymethyl) -2, 7-dimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(3S,7S,10S,13R) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -6- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4- (trifluoromethyl) benzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -2, 3-dihydro-1H-inden-1-yl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12R) -12-benzyl-1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -5- (methoxymethyl) -2, 7-dimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -5- (hydroxymethyl) -2,7, 10-trimethyl-12- ((1R,3S) -3-methyl-2, 3-dihydro-1H-inden-1-yl) -1,4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (pyridin-2-ylmethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((R) -2, 3-dihydro-1H-inden-1-yl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- ((R) -1-hydroxyethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-13- (4-chlorobenzyl) -6- (2, 4-dichloro-6- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -3,7, 12-trimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,10S,13R) -6- (5-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -10- (hydroxymethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -2, 3-dihydro-1H-inden-1-yl) -5- (methoxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -2, 3-dihydrobenzofuran-3-yl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -5- (hydroxymethyl) -12- ((R) -7-methoxy-2, 3-dihydrobenzofuran-3-yl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(3S,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((2- (2-ethoxyethoxy) ethoxy) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 4,6,9, 12-pentazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -7- (2-fluoroethyl) -10- (methoxymethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(2S,5S,8R,12R) -12-benzyl-1- (4-chloro-2- (3, 5-difluoro-4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -5- (hydroxymethyl) -2,7, 10-trimethyl-12- ((R) -1-phenylethyl) -1,4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12R) -12-benzyl-1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- ((S) -1-hydroxyethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -7-methoxy-2, 3-dihydrobenzofuran-3-yl) -5- (methoxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -3, 3-dimethyl-2, 3-dihydro-1H-inden-1-yl) -5- (methoxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12R) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) -6- (2,2, 2-trifluoroethoxy) benzyl) -8- (4-chlorobenzyl) -12-ethyl-5- (hydroxymethyl) -2, 7-dimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -10- (3, 3-difluoropropyl) -12- ((R) -2, 3-dihydro-1H-inden-1-yl) -5- (methoxymethyl) -2, 7-dimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12R) -12-benzyl-1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -5- (methoxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -2, 3-dihydro-1H-inden-1-yl) -5- (methoxymethyl) -2, 7-dimethyl-10- ((1-methylcyclopropyl) methyl) -1,4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12R) -12-benzyl-1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -10- (3- (dimethylamino) propyl) -5- (methoxymethyl) -2, 7-dimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12R) -12-benzyl-1- (4-chloro-2- (3, 5-difluoro-4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -5- (methoxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8S,12S) -8- (4-chlorobenzyl) -12- ((S) -2, 3-dihydro-1H-inden-1-yl) -1- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-ethylbenzyl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12S) -8- (4-chlorobenzyl) -12- ((S) -2, 3-dihydro-1H-inden-1-yl) -1- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-ethylbenzyl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 8, 11-trione;

(2S,5R,8R,12S) -8- (4-chlorobenzyl) -12- ((S) -2, 3-dihydro-1H-inden-1-yl) -1- (2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-ethylbenzyl) -5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(3R,7S,10R,13R) -3-benzyl-6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,10S,13R) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -6- (4- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -2-fluorobenzyl) -10- (hydroxymethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -13- (4-chlorobenzyl) -3- ((S) -2, 3-dihydro-1H-inden-1-yl) -6- (4- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -2-fluorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(2S,5S,8R,12R) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12-ethyl-5- (hydroxymethyl) -2, 7-dimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -2, 3-dihydro-1H-inden-1-yl) -5- (methoxymethyl) -7, 10-dimethyl-2- (2-morpholinoethyl) -1,4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S) -N- ((3R,8S,11R) -3-benzyl-11- (4-chlorobenzyl) -10-methyl-2, 5, 9-trioxa-6-oxa-1, 10-diazabicyclo [9.3.1] pentadecan-8-yl) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionamide;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -2, 3-dihydro-1H-inden-1-yl) -5- (methoxymethyl) -7, 10-dimethyl-2- (3-morpholinopropyl) -1,4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12R) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12-ethyl-5- (hydroxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12R) -12-benzyl-1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -2,7, 10-trimethyl-5- (2-oxapropyl) -1,4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S) -N- ((3S,8R,11R) -8-benzyl-11- (4-chlorobenzyl) -10-methyl-2, 6, 9-trioxa-5-oxa-1, 10-diazabicyclo [9.3.1] pentadecan-3-yl) -2- ((4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) amino) propionamide;

(2S,5S,8R,12S) -1- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -2, 3-dihydro-1H-inden-1-yl) -5- (methoxymethyl) -7, 10-dimethyl-2- (4-morpholinobutyl) -1,4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(2S,5S,8R,12S) -2- (3- (azetidin-1-yl) -3-oxapropyl) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- ((R) -3, 3-dimethyl-2, 3-dihydro-1H-inden-1-yl) -5- (methoxymethyl) -7, 10-dimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -3-isopropyl-7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(2S,5S,8R,12R) -1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -12- (dimethylamino) -5- (methoxymethyl) -2,7, 10-trimethyl-1, 4,7, 10-tetraazacyclotetradecane-3, 6,11, 14-tetraone;

2- ((2S,5S,8R,12R) -12-benzyl-1- (4-chloro-2- (4- (1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-imidazol-5-yl) phenoxy) benzyl) -8- (4-chlorobenzyl) -2,7, 10-trimethyl-3, 6,11, 14-tetraoxo-1, 4,7, 10-tetraazacyclotetradecan-5-yl) acetic acid;

(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butyl (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((cyclobutyl (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3-cyclobutyl-10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butyl (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (cyclopropylmethyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butyl (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- ((1-methylcyclopropyl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (cyclopropylmethyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (2, 2-difluoropropyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) -13- (4-chlorobenzyl) -3- (cyclopropylmethyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((ethyl (1-methylcyclopropyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((cyclobutylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (cyclopropylmethyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (cyclopropylmethyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (cyclobutylmethyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-4-oxa-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- (azetidin-1-ylmethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (2, 2-difluoropropyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((cyclobutyl (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7-methyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (3, 3-difluorocyclobutyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (2- (4- (2- ((tert-butyl (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chlorobenzyl) -13- (4-chlorobenzyl) -3- (cyclopropylmethyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (2- (4- (2- ((tert-butyl (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (cyclopropylmethyl) -10- (hydroxymethyl) -7-methyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (3, 3-difluorocyclobutyl) -10- (hydroxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (3, 3-difluorocyclobutyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (2- (4- (2- (aminomethyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (3, 3-difluorocyclobutyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

2- (((3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-2, 5,8, 11-tetraoxo-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecan-3-yl) methyl) -6-methylpyridine 1-oxide;

(3S,7S,10S,13R) -6- (2- (4- (2- ((tert-butyl (methyl) amino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -4-chloro-6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (3, 3-difluorocyclobutyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3R,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- ((6-methylpyridin-2-yl) methyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -3- (3, 3-difluorocyclobutyl) -10- (methoxymethyl) -7, 12-dimethyl-1, 6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (tetrahydro-2H-pyran-4-yl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- ((difluoromethoxy) methyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7R,10S,13R) -6- (4-chloro-2- ((6- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) pyridin-3-yl) oxy) -6-fluorobenzyl) -13- (4-chlorobenzyl) -10- (methoxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

(3S,7S,10S,13R) -6- (4-chloro-2-fluoro-6- (4- (1-methyl-2- ((methylamino) methyl) -1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -7, 12-dimethyl-3- (2,2, 2-trifluoroethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone; and

(3R,7S,10S,13R) -7- (2-aminoethyl) -3-benzyl-6- (4-chloro-2- (4- (2- ((dimethylamino) methyl) -1-methyl-1H-imidazol-5-yl) phenoxy) benzyl) -13- (4-chlorobenzyl) -10- (hydroxymethyl) -1,6,9, 12-tetraazabicyclo [11.3.1] heptadecane-2, 5,8, 11-tetraone;

21. The compound according to claim 1, selected from:

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

23. The pharmaceutical composition of claim 22, further comprising at least one additional pharmaceutical agent.

24. The pharmaceutical composition according to claim 22 or claim 23 for use in the treatment of a PCSK 9-mediated disease or disorder.

25. A method of modulating PCSK9, comprising administering to a patient in need thereof a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof.

26. A method of inhibiting PCSK9, the method comprising administering to a patient in need thereof a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof.

27. A method of inhibiting PCSK9 activity comprising administering to a patient in need thereof a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof.

28. A method of treating a PCSK 9-mediated disease or disorder, the method comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein the PCSK 9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

30. A method of reducing LDL-C in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, thereby reducing LDL-C in the patient.

31. The method of any one of claims 25-30, wherein administration is oral, parenteral, subcutaneous, by injection, or by infusion.

32. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use in the treatment of a PCSK 9-mediated disease or disorder.

33. A compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, for use in the treatment of a PCSK9 mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

34. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a PCSK 9-mediated disease or disorder.

35. The use of claim 34, wherein the PCSK 9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

36. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease associated with the inhibition of PCSK9 activity.

37. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for the treatment of a disease associated with the inhibition of PCSK9 activity.

38. The use of claim 37, wherein the disease associated with inhibition of PCSK9 activity is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

39. A method of making a compound having formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,

(g) alkylating a compound having formula (IIa) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,

wherein R is₅Is H and R₉As defined above for formula (I),

(h) reacting a compound having formula (IIb) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof with an acid in a solvent, followed by Boc₂Reacting O with a base to form a compound having formula (IIc),

(i) Alkylating a compound having formula (IIc), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof, using an alkylating agent in a solvent and optionally a metal oxide, to provide a compound having formula (IId),

40. The process of claim 39, wherein the solvent in step (a) is DMF.

41. The method of claim 39 or 40, wherein the temperature in step (a) is about 0 ℃.

42. The method of any one of claims 39-41, wherein the acid in step (b) is trifluoroacetic acid (TFA).

43. The method of any one of claims 39-42, wherein a metal oxide is used in step (c).

44. The method of claim 43, wherein the metal oxide is silver (I) oxide (Ag) ₂O)。

45. The process of any one of claims 39-44, wherein the palladium catalyst in step (d) is tetrakis (triphenylphosphine) palladium (0).

46. A method of making a compound having formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,

wherein R is₅Is (C)₁-C₆Alkyl) andR₉is as defined above for formula (I), with a palladium catalyst and N, N-dimethyltrimethylsilylamine in a solvent to provide a compound having formula (II).

47. The method of claim 46, wherein the solvent is in dichloromethane.

48. The method of claim 46 or 47, wherein the palladium catalyst is tetrakis (triphenylphosphine) palladium (0).